The Binding of Isaac/WMG

Larry, Jr is a successful experiment of a human centipede
This boss has a kind of similar behavior to the Centipede, and he (or rather they) shits everywhere while you fight him, thus the WMG. Well, if he isn't human now, he might have been at some point.
 * Also, try looking carefully at his head. He's crying.
 * Sometimes when you shoot the body, Larry Jr. splits into two. Now where would the other head come from? From the body. It's not separate segments. These are actual heads connected into a centipede.

God never demanded a sacrifice. Isaac's mother was having delusions.
Some analyzers of the original Christian myth say that God stopped Abraham's hand when he was about to kill Isaac because God had never asked for a sacrifice, and Abraham was just imagining things. Following that line of thought, perhaps Isaac's mother in the game was also the same way.
 * Given the Halloween Update,
 * Either that, or it's supposed to mirror the story as it is -- God asked her as a test of faith. The reason He.

The 11th Ending is a Time Loop from Future Isaac to be later found by his younger self in the 10th Ending
Thus making sure that its younger self will wake up from the illusion of salvation from his mother by the bible that God used or that he was making any progress at all by going on and on with killing his mother in self defense. In the end he will realise that there is only death as a escape from the inevitable sacrifice by the hand of his mom and God would not save him either
 * This is sort of supported by the fact that XXX has the same nightmares as all the other characters, and that Mom still calls him 'Isaac'.

Isaac is an aborted fetus
His mother heard the Voice of God when she was pregnant, and sacrificed her unborn child. She's later been plagued by delusions of what she's done and what happened to him and where he is now, and the game is made up of her hallucinations.
 * Supported by The Wire, It Lives: Your Past and Future Self, and the 11th Ending.

Almost every enemy is a possible Bad Future for Isaac
Many items end up making Isaac look like certain enemies. Or, alternatives, many enemies look like Isaac with certain items. The Seven Deadly Sins is where it's the most obvious, and with a few items from the Devil Room, he begins to strongly resemble as well. Assuming the above WMGs are true, why stop there?

Isaac is an abused, unwanted child, and/or the spawn of Satan -- Either way, he wants to return to the womb and start over
He's naked. He has no possessions. His weapons are all body fluids. Most enemies resemble Isaac. "It Lives" IS Isaac as a fetus. Every form of Isaac is him dressed as a potential version of Isaac in the future. XXX/??? the Dead Baby -- to whom Isaac reacts in absolute horror -- is obtained AFTER YOU KILL ISAAC'S FETUS FORM. Every power-up mutates Isaac as well, representing future versions of him.

If we assume he's the spawn of Satan, it explains the offers and why he fights him at the end -- it's a battle for control over his destiny.

In the end, Isaac has a showdown with Satan and finds a final chest... which cycles through all the personas he has taken and returns him to his room. What's in the chest, the same sort of chest that's found in the Womb? A chance to start over -- Isaac can either keep his current life or try a new one (he chooses the latter).

Forget "Bad Future" -- Isaac doesn't even want his Bad Present.
 * Isaac being the spawn of Satan, or some other kind of demon, is supported by the ending unlocked by beating

Isaac's mother abuses him and takes away his clothes because he crossdresses.
Either the "voice of God" thing was made up entirely, or her disturbed mind created it as a justification for extreme measures to prevent her child from being "deviant". Once she saw that he was still managing to jerry-rig costumes together, she decided the only way to stop him was to kill him outright.

Everything you play is Isaac's imagination.
Okay, so, Isaac's mother does take away his toys and later thinks she has to kill him. He runs away in the basement and, while his mother is chasing him, hides in a chest and starts imagining things to pass time. However, because he lost his toys and his mother wants to kill him, Isaac can't think of anything happy, so his imagination (in other words, the game) is filled with his interpretations of all the nasty stuff he overheard from his mother's christian broadcasts (or he is just a weird child, believe in what you want to believe). The unlockable characters are all imaginary friends he makes up for the fantasy as he plays, and so are the unlockable items.

The part when you beat Mom for the first time in the game is actually her closing in on him and searching for him. Then,the bible falls on her head, but that does not kill her. Rather,it knocks some sense in her head, and a The End or Is It ending is actually just made unnecessarily ominous. Isaac's mom actually apoligizes to him.

The ten mom kills that follow in the game is her returning Isaac's toys to him. However, he finds the imagination game to be a lot more fun that his toys were, so rather than playing with the toys, he uses them as an inspiration for some new elements for his fantasy. The final ending shows Isaac just returning to do what he did before: imagine.

Hey, does everything here have to be as grimdark as the game itself?

EDIT: Now that the Wrath of the Lamb is out, I guess I have to update this.

Isaac is growing up. He is getting now types of toys, new ideas and is slowly nearing puberty. I say this because the items and bosses seem to be a bit more "mature" and different (see: puberty pills, stem cells, those faces + hearts, stuff generally not related to Bible, new rules, new floors et cetera. However, he realizes that he can beat all the bosses he thinks up, so he makes himself a new boss,the only one that might have a chance to defeat him: himself.

After Isaac does that, he tries to find new ideas and begins to realize that he is slowly outgrowing his game. He sees his devil form in the mirror as a lot more awesome form of him that, well, he just won't be able to be like anymore. That kinda correlates to the person playing the game realizing that he/she is running out of things to do.

Alternatively, Isaac is beginning to understand just how twisted some of the stuff he made up is.
 * Including the toy he uses to hang himself?
 * Considering what monsters he made up, something like that is kinda par for the course.
 * I desperately want this to be true. I really do.
 * Perhaps Isaac is so obsessed with the imagination game that he starts spending all his time in the chest and begins to ignore the real world and his basic needs for survival. The Dead Baby is a warning from his mind that if he doesn't stop soon, he'll end up like it.
 * Wouldn't that explain neatly why all the rooms you explore all have the exact same shape as the chest?

First ending is the real ending.
This is similar to above theory: As we can see, Isaac drew the opening narration pictures and the "Bible kills mom" ending on the paper. Intro was Isaac recapping to himself what was happening, the actual game was hallucinations/imagination and in the end he imagines himself a happy ending and draws it. But since its imagination, that doesn't really kill mom and she comes to the basement.

Issac has superhuman abilities, and when he grows up he will become almost invincible, and the family were mostly threatened by the mother's state.
Issac, from birth, had to endure hardships. After that, his father probably got sick as all hell. possibly nymphomaniac of the millina to keep that up. Most kids were broken before they even fully formed, leaving us the eyeless (taken out before they could fully form their eyes), headless (got so nasty a cranial infection that it had to be removed), and then genetic issue (the fly hives and the like being unable to physically take care of themselves). Ivan was so tough that he was able to resist all the problems, and his genetics were sound. Because he had to go through what is basically a warrior's challenge at birth, he was so tougher for that, but because of that he was too awkward around other kids because he never wanted to interact physically, so they teased him.

Isaac is the Anti Christ, and the game is a Batman Gambit from God to make him into an Anti Anti Christ.
This may or may not tie in with the "in his imagination" theory, i.e. it might be images, dreams or hallucinations sent to Isaac from God. Specifically, by enduring the horrors of his mother's excessive fundamentalism, he will be protected from becoming a Knight Templar when he discovers his powers; at the same time, fighting the monsters in the dungeon (and eventually Satan himself) both physically and spiritually gives him the means to fend off those who would do him harm, man or demon. Once he finally triumphs over Satan, God either erases the events from reality and makes them as nothing but a daydream (the memory of which will nonetheless keep Isaac strong in the years to come), or makes the dreams/images stop plaguing him so he can rest.
 * Supported by the ending unlocked by beating at the end of Wrath of the Lamb.
 * Note also that as of Wrath of the Lamb,

EVERYTHING is in Isaac's imagination, even his mother trying to kill him. His mother's been dead all along.
Perhaps Isaac's mother dies in her chair while watching her Christian shows, and the trauma of either seeing her die or finding her corpse drives Isaac crazy. Add in whatever madness that was being broadcast on the TV, and all those things combined would probably be enough to cause a little kid to snap.

Isaac's mother removed his penis.
His penis is visible in flashbacks, but not during the game. At some point before the voice's third declaration, Isaac's mother thought of another way to help free Isaac from sin.
 * Then how can he pee?
 * Terrible!
 * He can CRY farther than he can piss. This is not normal.

The basement under Isaac's house, for some reason, is Hell
Kind of an obvious one, with all the aborted/stillborn/mutated/whatever siblings all over the place. Nothing here dies.

It's all in Mom's imagination.
Whether by miscarriage or abortion or accident or murder, Isaac is dead. Mom creates the events of the game within her head, starting with God's commandment that Isaac should be killed, to rationalize Isaac's death. Her fears tell her Isaac has fallen into Hell; her self-blame and self-loathing place her as a monstrous enemy of Isaac.

It´s all a Xanatos Gambit of
Mom never heard God´s voice. It was, who tried to corrupt someone. The possible outcomes: -Mom kills Isaac, corrupting her soul. -Isaac kills Mom, probably having collected enough "Devil-Items" to be corrupted -A monster kills Isaac, can try the same with another family And Isaac battling the final boss is because he found out about that gambit and is seeking revenge.

Envy´s and Pride´s names are swapped.
Just think about it: Envy just floats around, smiling and being proud enough to not even attack, while Pride spawns bombs and energy-ray-things, generally being destructive, because he´s probably envious of what others have and wants to destroy it.

Mom is simply getting a second child
When his Mom gets pregnant, he thinks she won´t pay attention to him anymore, thus the taking of his stuff. He begins to feel unwanted, believing his mother wants to get rid of him and tries to abort the fetus himself (It Lives!), even succeeding in his task. Then he realises that he´d love having a new brother or sister and thinks, the dead baby would be alive. It would even explain the overabundance of dead babies in the basement!
 * Jossed By one simple fact: Word of God has confirmed that It Lives is

His mother wants to kill Isaac because of the father.
Note that the opening narration specifically states that Isaac lives alone with his mother, with no father to be found (and, indeed, a father would presumably attempt to defend him). With his mother's strong Christian roots, a divorce seems unlikely, which leaves two likely scenarios:
 * Isaac is a product of rape, and his mother goes insane and attempts to "protect him from sin" because she goes insane with the fear that he might turn out like his father,
 * Or Isaac's father and mother truly loved one another, and his father's death led to his mother going mad from despair.
 * The latter could indeed be possible, if is any indication.

The dead corpse in the shops is really Greed.
They have the exact same skin tone, Greed wears the noose cut off... It's like he watched you descend from the Basement to the Depths, where he may fight Isaac out of spite. Note, Depths 2 is the last level for a shop, and that tends to get replaced by Greed. The Womb and Sheol don't have shops. Probably tried to pull a You Have Outlived Your Usefulness on a potentially overpowered kid?

Isaac's Mom isn't religious at all.
The intro story and first ending are apparantly narrated by Isaac inside his head, as each of them are his own drawings, and yet they are filled with religious themes and his mother's chanting (note that when she talks ingame, her voice is different, and she only says 'Isaac'), along with the bible killing her. Not only that, but there are many indications of child cruelty ingame ('Dinner' being Dog Food, as an example) which shows that his Mother has been deranged and abusive for a long time before her psychotic episode despite the intro describing their lives beforehand as 'happy'. The religious themes are there because Isaac himself is religious (as people in desperate situations, such as an abusive childhood, tend to be) and the links to the Binding of Isaac story are just his naive attempts to justify his deranged psychopath of a parent. Mom bursting into the room in the 1st ending is just a stinger and not a genuine event, so the 1st ending leads straight into the 11th, where Isaac himself does the only thing he can think of to get away from her and locks himself in the chest, suffocating or starving to death. The game is his confused and terrified attempt attempt to put everything together and remember his life as he waits inside the chest, hence the muddled religious themes and references to an abusive childhood in almost every aspect of the game.

Everything actually turned out fine in the first ending.
In the latest trailer for Wrath Of the Lamb, Isaac's letter to Guppy states that the basement is "different". This implies that he has been there multiple times. Perhaps Mom didn't actually intend on killing Isaac at the end of the first ending? For all we know, she knows Isaac's been to the basement and was offering the knife to him in case he went again?

Basically, ever since then he's been making frequent excursions to the Basement and beyond. But why does he keep fighting his mother, you may ask? Well, that leads to my second WMG...

"Mom" isn't actually Mom at all!
It's a demon taking her form! Basically, Mom wasn't going crazy at all. Instead, a demon had captured her and disguised itself as her. It used Religious Fervor as an attempt to get Isaac to forsake it. And even if he didn't, there was still a chance of murdering a small child and possibly his mother. So, essentially, after Isaac fights the demon, his mother is freed, and she finds Isaac in his room, drawing his adventure down to preserve the memory of it. However, the knife was meant to attack the demon since she thought it was still around.

The demon keeps coming back, resulting in Isaac continuously going into the basement to fight it again and again. Eventually, he heads to Sheol to fight Satan, realizing he needs to destroy the demon at the source. The treasure chest Isaac entered at the end was actually the only way to escape, as opposed to Isaac essentially committing suicide.

Now why would I make these 2 WM Gs, you ask? Because Dammit, this story is just too fucking depressing.

Isaac's mother never tried to kill him, it's all made up by resentful Isaac
Mother does think Isaac has been "corrupted by sin" -- because she saw the things he's been drawing, those macabre scenes (seriously, have a look at the pause menu) and monster designs. Immediately, she takes away his toys, which surely are to blame for Isaac's behavior. She has him read the bible instead.

Isaac is not easily placated. Inspired by the bible, he makes up several characters to play with. When he encounters the story of Isaac, whose name he shares, he starts imagining a story in which his mother wants to sacrifice him, but he escapes, regains things he used to play with before his mother took them away (and other things he thought that were cool), and defeats her with them. Since he's just a little boy, the plot is simplistic and somewhat nonsensical, but there are cool monsters and stuff!

He finishes the story, but still is bored, so he continues, not caring about the plot at all but just making up new cool items. Things also get a little Freudian...

At one point he decides it's so fun, he might as well throw in him defeating Satan.

The story, especially with Wrath of the Lamb, is a metaphor for Isaac's coming of age.
Isaac is beginning to enter his teenage years, probably coping with depression, and the entire game is allegorical. To wit:
 * Isaac's mother is not abusive, nor attempting to kill him. This is a metaphor for increased tension between the two; as a single mother, she gets the brunt of his depression, outbursts, etc.
 * When fighting, he is in fact hurting her with words, possibly via an argument. Similarly, may be a metaphor for either suicidal thoughts, or claiming he wishes he'd never been born.
 * Puberty pills can be found after Wrath of the Lamb, suggesting that Isaac is changing more and more.
 * All of Isaac's different personas aren't "playing pretend" in the traditional sense- rather, he's grappling with his identity, and trying on several different personas (Eve is a stint with goth/emo, Cain and Samson with being "badass" and/or a delinquent, Judas with being cool and classy, and Maggy with being cheerful and "normal"). He's likely also grappling with gender issues, which his traditionalist mother either doesn't understand, can't accept, or doesn't even know about.
 * There are final bosses with Wrath of the Lamb, all potential outcomes to a crisis of faith as he questions his beliefs.  represents Isaac staying a devout Christian, and possibly making peace with his mother.  represents Isaac coming to terms with sin, and embracing agnosticism/atheism/a non-Christian faith.

Isaac suffers from Dissociative Identity Disorder.
First of all, if the majority of the game is taken at face value, Isaac has clearly had an abusive childhood- the sort of experience believed to foster DID. The other characters are, in fact, alternate personalities, who fight his mother in his place as a coping mechanism. In the, whichever personality is, in fact, subsuming the real Isaac. Assuming Isaac beats, then a Split Personality Merge results instead.

Isaac's Dad abandoned the family a long time ago
In Wrath of the Lamb, you can pick up an item called Dad's Key. This item unlocks all the doors in any room, and is primarily designed to allow you to run away from conflict.

Conquest is, in fact, War having taken a level in badass.
Of the original Four Harbringers of the game, War is almost always considered the easiest to fight - this in spite of being, you know, the personification of ALL COMBAT. Conquest only appears on the later levels, after you've probably defeated War, and the distinction between Conquest's and War's domains is very minimal (hence why Conquest is replaced with Pestilence in most modern depictions of the Horsemen in the first place). Finally, their abilities are very similar:
 * War is the only one of the "Harbringers proper" to charge multiple times in a row, and will often charge after a standard attack. Conquest has the unique ability to create multiple bodies to charge at once.
 * War can raise his horse to the sky to summon troll bombs. Conquest can also raise his horse to the sky, summoning pillars of holy light.

Completing and using The Polaroid brings the Stable Time Loop, and Isaac's suffering, to an end.
Completing with six characters unlocks an item called the Polaroid. Take it into the fight with, and rather than fighting him, you instead fight   After this, Ending 12 makes a lot more sence.

When he grows up, Isaac will enter a radio contest and win a ticket to Albuquerque.
He refuses to leave without a ten-inch saxophone, a twelve pound bowling ball, a glow in the dark snorkel, and a chainsaw, because they give him super powers. Like the ability to survive a plane crash.

Isaac is Isaac Clarke
Being very young during the events of this game, he is quick to block it all out of his mind after it's over. However, the experience he gains from fighting all of these horrors stays with him into adulthood, enabling him to instantly Take a Level In Badass when he has to fight Necromorphs.