As I have mentioned before, I am a huge fan of Stargate (the movie, the TV show, and the RPG). At our last D&D session, our characters, who are traipsing around the various levels of Perdition in search of an artifact, stepped through what was basically a fantasy version of a Stargate.
So, what if the party were part of a guild that had discovered a network of inter-dimensional portals, and their job was to go through these portals and find out what was on the other side? Find new or lost artifacts? Search for evidence of lost civilizations and gods? Find some kind of ally or weapon to help their home world fight off a demonic invasion?
The possibilities are pretty endless.