Screwing with their characters without their consent. Changing their alignment, forcing them to take levels in this and that, causing paladins to fall, hacking off their limbs when regeneration is not easily available, raping them, et cetera.
Remember, the plot is the DMs, but the characters belong to the players. You can set up the world however you like to make your cool adventure happen, but always, always, always remember that the players decisions are final on what their character does.
If it's something particularly stupid, they can and will face consequences in the world for their choice, but it's still their choice. If you take this aspect away from them, it *will* ruin the game.
Back from a lengthy vacation from Giantitp. I've been dabbling with 3d printer technology and game design, PM if you're curious.
"World domination is such an ugly phrase. I prefer to call it world optimization."