I'd like to see three setting lines developed:
1) A new sandbox setting - relatively vanilla but with different regions embodying different styles of play - say, a Hyborian-esque North, a Dalelands-esque classic fantasy region, an undiscovered jungle region, etc. This would remain in the "eternal now" with no advancing of the timeline and be, in a sense, the archetypal D&D fantasy setting with a host of classic and new adventures set in it. Products would include something akin to the original FR "Grey Box", regional guidebooks which could include hexcrawling guidelines, and then encounter books and individual adventures.
2) A new metaplot setting(s) - something along the lines of Dragonlance - a setting built for story. A massive metaplot Adventure Path (or "Highway", more like it) could be developed over a couple years, and then a new metaplot setting sometime after that. The world could be played without following the metaplot, or after it was finished, but it would be designed around the story. Products might include an initial box set with a DM's guide, player's guide, and character creation guide, then the adventures, then maybe a couple concluding books at the end of the line - a monster book including new creatures and a campaign world book that facilitates play after the metaplot is over. Then, after maybe a 2-3 year cycle, a new setting would be developed with a new metaplot.
3) Classic Settings - Hardcovers or box sets detailing a classic setting from the TSR/WotC archives. These could even be setting neutral with an appendix on how to "Nextify" it.
Now of course none of the above is likely to happen. More likely we're going to see some kind of re-hashing of old settings, which is really too bad. My outline above provides the best of both worlds - new treatments of old classics, but also new settings. I just don't see the point in re-packaging the same old FR material from the last 25 years, or Eberron from the last 10. If people want to play in the FR there is plenty of material available.
On a side note, 4E really missed the boat on the importance of living, thriving settings - as evinced by [notranslate]Pathfinder[/notranslate]'s success, which is largely due to Golarion and the living quality it provides for the game. A game needs setting, a story needs place - 4E's was vague, disjointed, and undeveloped.
