Spice and Wolf/WMG

Holo is Haruhi, and Lawrence is Kyon.
Haruhi destroyed our world and created a new one with fascinating economics.

Holo is a prototype Terminator.
In it's time travel experiments, Skynet sent back Holo as a T-1000 variant that can create the illusion of additional mass. However she was sent back too far and took the form of the local harvest deity as to not arouse suspicions. Her being wise is due to an extended neural net. Everything she told Lawrence was a lie.
 * She's awfully playful for an emotionless chunk of metal.

Holo is C.C., and Lawrence is Lelouch.
The series takes place in Lelouch's mind After the End of Code Geass: Lelouch is finally brainwashed for good by the Emperor and trapped in a fantasy world for the rest of his life. Holo may be a complete figment of his imagination, or her contract with Lelouch may be allowing some sort of reflection of herself to invade his dreams. Lelouch and Lawrence share a VA, after all. Like so. (This theory was originally written to explain what happened to Lelouch after the cliffhanger ending of the first season.)
 * Holo might be Karen, who was sent by CC to retrieve Zero. Kallen and Holo share a voice actress, too. But Kallen is hardly a wise wolf; C.C. and Holo have more similarities.
 * of Code Geass R2 generated a fresh burst of fanart of this theory. Maybe it's not just in his mind after all.

Holo has retired to Gensokyo in the modern age.
Lawrence is only human, and can only live so long. Over the past few centuries, Holo found other interesting guys to hang around and talk economics with, but the recent chain of economic crises and her sadness at losing so many friends (including the others of her kind in the North) has caused her to seek out a refuge from all these. A nice lady in a purple dress told her to go to Hakurei Shrine...

The series is set in the same universe as Princess Mononoke.
Holo is a distant relative of the Moro's tribe. In the equivalent of Europe (the two are set in fantastic and little off versions of Japan and Europe) in this world only the greatest, most powerful and the most cunning of animal gods survived the spread of the human civilization, and especially the Church's influence, resulting in even greater size than those seen in Princess Mononoke, as well as the learned ability to shape-shift in order to avoid attention. The legend of the Moon-Eating Bear destroying Yoitsu is based on another incarnation of the Forest God/Deer God being decapitated by foolish humans, resulting in a similar catastrophe as seen in the movie.

"Merchant Meats Spicy Wolf" is more of a morbid hint of future events than we give it credit for.
Screw the more obvious implications of Lawrence "meeting" Holo during the night. For all we know, she, for some reason or another, passes away at the end of their journey in her wolf form, and pays back her debt to Lawrence with her dying breath by allowing him to convert and sell her remains as raw, consumable wolf meat...preserved and flavored by spices, of course.
 * After volume 17 of the light novels we DO know which connotation was meant by the phrase's double entendre.

The series is in the distant past of American Gods.
The reoccuring theme of the world no longer needing Pagan Gods due to the spread of Christianity is very similar to the decline of the ancient Gods in the midst of the created modern Gods. Holo maintains a moderately high level of power because the small village still honours her with the festival and some basic lip service even if they are in decline. Within time the world will forget all about Holo and she will become a forgotten God and eventually pass into nothing.

Holo goes on to become Terra West.
Being The Last of Her Kind Holo stayed with Lawerence until he eventually died of old age. Depressed by the loss of her mortal love as well as that of her people Holo set about traveling the world, even journeying to the New World where she met Listens To Wind who kindly taught her the magic needed to let other mortal become wolves to keep her company. Her time with Listens To Wind taught her that a lot of magical beings are not as benign as herself and she sought do what she could about trouble makers by training groups of werewolves like the Alphas and keeping larger lupine threats like the Loup Garou as contained as possible.

Lawrence will outlive Holo.
It's a perfect balance of romance and realism. Holo, after centuries of loneliness, will die during a happy time of her life, in the arms of the man she loves (maybe leave a baby behind... maybe even die giving birth). It always sucks for the survivor, but Holo's been a survivor for too long, I don't think she deserves to die alone. Plus, her death isn't all that unrealistic, considering her life force lies in a small bag of wheat, which, as she mentioned, can be burned, eaten, ground down, etc. Lawrence, meanwhile, will be saddened by his loss, but happy for the memories, and will finally open his shop.

Holo the wise Wolf is actualy Holo the wise FOX
Her ears and tail are red this -vs- this. but for the counter argue try this it's the entire page since I couldn't personally find one that looked close enough to the Wise Wolf
 * She's a wolf. In her human form her ears and tail may resemble a fox, but there is no fox alive that even remotely resembles her wolf form.

Few thousand years down the line, Holo's descendant will be Kamina
"Just look at my ears and tail. Can you not tell I am a very proud wolf? Not only can my ears hear disaster, they can also detect lies. When people speak of Holo the wise wolf, they are referring to none other than me."

"The reputation of team Gurren echos far and wide! When they talk about it's badass leader! A man of indomitable spirit and masculinity, they're talking about me! The mighty Kamina!"

These two phrase just got me to compare the two.