YMMV / Desktop Dungeons

• 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.
• Goddamn Bats: Bandits are weak, but curse you every time they hit you. Curse stacks must be burned off by killing monsters (one for every level), and as long as you have any curse stacks, you take full damage from attacks. Classes that rely on damage resistance, like monks, are in deep trouble.
• 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.
• That One Sidequest: The Thief Silver quest requires extremely careful rationing of resources, plus tremendous luck, to stand any chance against the boss. The only enemies you stand a chance against at level 1 still require a potion and several boosters to take down, and are at the opposite side of the map, past a bunch of other enemies (eventually leading to an Obvious Rule Patch that showed their locations so the player had some direction at the start of the map).