Real world scientists have accidentally opened a tear in the fabric of reality, transporting their laboratory into the game world. Unable to repair and/or refuel their equipment in this (to their minds) primitive world they are now trapped.
The local band of 'nasties' (goblins / orcs / whatever) lives in relative peace with the local population.
Along come the PCs and go through their usual heroic monster bashing routine, wiping out the nasties and pinching all their stuff, then continue on their way.
Problem is, they don't kill ALL he nasties. The survivors want revenge and, after spending a few months recovering, start to take it in their own inimitable style (which is not unlike that of the PCs come to think of it).
Next time the PCs are in the area they find themselves VERY unpopular with the townsfolk.
A plague has hit the local area.
In humans it affects only the most vulnerable, the children and the very old, and even than it's little more than a summer cold. 24 hours of sniffles and then it's gone, barely noticeable really.
To sheep however it is fatal and the whole economy of the area is in serious trouble. If this keeps up the area could well be facing famine.
Somebody (enter the PCs) must find the rare herbs needed to make a cure.
In one region of a forest, all of the trees are identical, down to the leaves and the twigs. If the PCs carve something into one of the trees, it could mystically propigate until it covered all of the trees, or could vanish since it was not carved into the one true tree.