I always get kind of jealous when I hear about people who have been running different campaigns using the same setting, often for decades. I've never had any kind of serious, long term continuity in my games. The longest campaign I've ever run lasted about six months, maybe a little longer. And each of them has had, at least in theory, a completely distinct setting.
Which has had its advantages. I've been able to play with a lot of different kinds of things, and I like that. But I've never had a setting that I worked on for a long period of time, that grew from something basic and straightforward to something complex and multi-faceted. I like the idea of having a project like that.
What I always get stuck on is in building a cosmology that can acommodate "anything." Some kind of mult-world thing. That's always where I get stuck on setting design, when I do get stuck; I get the idea into my head that I have to have some grand framework supporting the whole thing, and I can never get that finished. And making it "multi-world" from the beginning always ends up seeming ridiculous and forced and opening up all kinds of weird problems that I don't want to deal with.
So I'm going to stop doing that.
The campaign I'm going to run this summer will end when the summer ends. And setting isn't going to be its main focus; I'm starting it off with Keep on the Shadowfell, may consider moving on to Thunderspire Labyrinth if that goes well and doesn't bore me out of my mind. (Though I'm going to need something to write for WoAdWriMo, and using an adventure written for the campaign seems like the obvious thing to do.)
If I end up needing setting material, I'm going to start with the 4e default setting and work my way out from there, see how well that goes. I've had some success with taking existing settings and tweaking them to my needs, and I want to see what I can do with the new setting. In general, though, I plan to focus more on developing my description and encounter-level skills than my world-building and scheme-planning skills.
But I'm going to have another campaign to run in the fall, and if I like 4e, and I like whatever setting evolves out of the summer campaign . . .
Well, we'll see.