I have some theories. In order of probability:
1: Spelljammer. It's D&D in spaaaaaace, which should be sufficiently different from the first three settings (pseudo-medieval Forgotten Realms, pulp Eberron and post-apocalyptic sword&sorcery Dark Sun), and equally importantly doesn't block out many existing character options (since it can act as a bridge between other settings). That bridge part is important too - it needs a few other settings to act as a bridge between, but now there are four, counting the implied setting of the core books. (And third-party publishers have had time to put out some 4E settings.)
2: Something original. Maybe a cop-out, but I think it's vastly more likely than any of the old settings right now. I have absolutely no guesses about it, but "generic fantasy" would compete with both Forgotten Realms and "Points of Light" (4E:s implied setting).
3: Al-Qadim. A man can hope. But seriously, "D&D Arabian Adventures" is also sufficiently different that it could sell. Some people keep saying that 9/11 made games about Arabs unpopular, but the video game industry has no such qualms.
My only misgiving about Al-Quadim is that the subject might be too thin to fill two books. Might fit better as a Dragon Magazine series, or a third party setting. The fluff would make or break it - "1001 nights" doesn't bring much new crunch.
3.1: Maztica. Same idea as Al-Quadim, minus 9/11. But the Middle East is cooler than Mesoamerica.
3.2: Kara-Tur. You get the idea.
Those are my three (point two) guesses. And now a quick rundown of what I don't expect:
Pseudo-Medieval Quasi-Europe, The D&D Setting: Dragonlance, Greyhawk, etc. Forgotten Realms needs to fade away first.
Already Folded Into Other Stuff: Planescape and Ravenloft. "Domains of Dread" is a running series in Dragon Magazine and Sigil has been cannibalized for use in both Manual of the Planes and Dungeon Master's Guide 2.
Too thin concepts: Council of Wyrms, Ghostwalk and maybe Birthright. Not enough stuff for two books.
Oh, and I hear the 2010 setting is Dark Sun. Nifty. It might be the first setting book I pick up for D&D.