Desktop Dungeons/YMMV

Game Breaker: Vampires. They lose health from exploring, which sounds bad but in context means they can explore as much as they want without penalty. They're immune to poison and have no mana to burn, have first strike and lifesteal to restore their health by killing weak enemies, they gain health from blood pools just like Blood Mages, and, most importantly, they cast spells using their health pool. A vampire with enough health, weak enemies and blood pools can atomize most any boss in the game with enough fireballs.
That One Boss: While it varies between classes (Physical fighters are screwed if they get the Tower of Goo, and magic-users are doomed if they get the Iron Man), Super Meat Man is probably the most Egregious example, with obscenely high HP. The only really reliable way to beat him is to have the APHEELSIK glyph or some form of inherent poison attack.