Looking back at my past campaigns, the ones I've had the most fun running (and which were arguably the most successful) were the ones where the PCs could take a fairly sandboxy approach to exploring a wilderness region. I'd like to develop a new campaign like this again one day, but what I could use for such a campaign is an interesting premise. I am ruling the following premises out:

• Adventurers plundering old ruins for profit: Too trite.
• Adenturer-archeologists uncovering the deep history of the region for academic bragging rights: A lot of fun, but I have done this before.
• Making the region "safe" for colonization and settlement: While the whole concept of "colonizing the frontier" provides plenty of interesting background drama for a campaign that I don't mind exploring, it is too ethically dubious to make the PCs take the side of the colonizers by default.

So, what other premises can you come up with that provide a justification for player characters to hang around a frontier region and explore it?