Despite it being out for some time, I only recently picked up Broodmother Skyfortress by Jeff Rients. And boy oh boy, it rules.
The basic premise of the adventure is that there's a floating fortress that hosts hammerhead shark centaurs that will fuck your campaign world up. (Awesome, right?) To facilitate this, Rients asks this question:
"What would happen if a bunch of giants showed up here and wrecked the place?"
He goes on to say that this might be painful if you are in love with your campaign setting. Nobody wants to spend hours lovingly crafting a world only to tear it apart. But this sacrifice is necessary--the pain of the loss of your favorite sites will let your PCs "get" the threat.
This is old writing advice: you have to kill your darlings (or, as one professor of mine put it, "drown those puppies.") In this instance, Rients is talking about the hammerhead centaurs. But really, this advice supersedes the adventure. This advice should be forefront in the minds of every GM out there.
You see, the PCs are the giants. And they are going to ruin your beautiful little fantasy world. They're going to set fires to your favorite inn, they're going to assassinate your aged kings and wicked despots, they're going to resurrect your forgotten gods, they're going to replace your strange cults with stranger ones.
When you're constructing your setting, your adventure, your quest, ask yourself: "What would happen if a bunch of giants showed up here and wrecked the place?" Be confident the PCs will do just that. And that's the point. That's why your players are playing your game. Let the PCs make a mess of your setting, and they'll keep coming back. Don't be afraid to kill those darlings.