As much as I'd like to critisize the Games Workshop business model, I think they have done one thing right in that they have 2 annually supported game lines (WHFB & WH40K) and generally rotate a 3rd game (blood bowl, necromunda, space hulk, etc) in support for long time fans and to introduce new players into a game where material isn't profitable enough for long term support. With the tremendous amount of backlog settings, I think a similar model might work for WOTC too. Were I given the reins of the brand the "big 2" would have to be 1 High Fantasy (Forgotten Realms) and 1 high adventure setting (Dragonlance or a new setting). While they might seem to be fairly similar on the surface, there is a distinction.
FR is such a vast world that other than on a Divine cataclysm scale (Time of Troubles & the lame Spellplague), even "Realms Shattering Events" don't have an enormous impact on the world beyond their immediate actions. Characters defeating the "big bad" of the Dalelands doesn't mean much to people in Amn and vice-versa. Magic abounds, elements of high fantasy exist in surplus, and it's a rich and vibrant setting that would be a huge waste to piss on... as much as I'd argue it was already done with 4E but there's a great core and a proven market for it.
I took Dragonlance as the example of high adventure to highlight as a setting where the metaplot is centered around a group of heroes and their actions. How this plays out on the table, is you center the player characters as being those heroes and your setting books are basically highly detailed adventure modules that bleed into each other.
Even if Dragonlance wasnt the setting of choice but a new creation, it might look something like this. Let's take the colonial game example a few posters described in this thread: The "old world" has been embroiled in centuries of warfare having depleted much of its (magical) resources, as the upper hierarchy has polarized into a very rigid status quo. It's just not possible for people to rise up through the ranks of society. Play up the oppressive natures of these realms where despair or malaise comes from the fact everyone has one time or another been affected by the constant struggles, war has ravaged and plundered the land, and what few great resources left are in the hands of a select few that use it as a method to keep themselves in power. Lo and behold, the PCs are hired in what might be the standard fetch quest and it turns out they find clues or hints of another continent. This first adventure should really hammer the dark feel of the original continent and how difficult life is there and try to nudge the players to want to leave for brighter horizons. Future books are based on players setting out on the voyage, landing on the new continent, setting a beachhead, etc. The books themselves detail these new areas but has an overarching storyline based on how the old world powers view this new development but also a sinister secret on why this continent was forgotten about so long ago, or what have you. It puts a firm emphasis on the actions of the PCs being integral or central to the metaplot.
The first campaign book gives you the mechanics portion of the setting with a general overview of the various old world nations, a fully fleshed out starting quest hub, and the main story adventure along with minor adventure hooks, npc descriptions and detailed descriptions to assist DMs with setting the tone or giving enough for players to go off the beaten path and not leave the DM scrambling.
The third rotating setting would follow the 4E model of releasing 2-3 books in a single year for a campaign. Here they can feel free to insert Birthright, Dark Sun, Ravenloft, etc and exploit their backlog just by compiling setting information, (re)-introducing mechanics that were part of those worlds, and maybe throw old time players a bone with some new fluff too. So essentially 1 big campaign setting book, a player's guide, and an adventure and away you go.
