I've never run a campaign with an overarching metaplot. I do story arcs (5-7 connected adventures, perhaps with other adventures thrown in between them) to explore themes or locales in my homebrew world that players show an interest in, but I don't have any overarching BBEG's in my world. Megalomaniacs and dangerous madmen to be sure, but there are dozens of them- not one overriding forces in the world.
The only metaplot game I've considered running would be for experienced gamers, in order to shake things up a bit. Basically, the PCs wake up in an abandoned monastery dressed in simple robes, with no memories of their previous lives. After exploring for a bit, they realize they were in a contained and magically shielded area, and when they get out, they find the remains of a violent battle in the monastery, with bodies littering the halls and surrounding land. A few clues remain as to who those involved in the conflict were, but its obvious from their garb and iconography, one group (the attackers) were from some holy order of a good-aligned church, while the defenders were mostly mercenaries. Since the PCs are all in the same situation to begin with (isolated and in a confusing situation), party unity should be easier to establish too.
As the PCs gain experience and try to piece together their missing identities, they would have occasional flashes or dreams of horrific events with them at the center of the trouble. They would also notice that so people react to them strangely (not trusting them, fearful, or with hatred), though most people treat them normally, and some "evil" people are inexplicably nice to them. Only late in the campaign (say 14th level in 4e), would the PCs realize they are actually resurrected major villians from the campaign world's past, brought back for some inexplicable reason. Apparently something went wrong with the resurrection ritual though, and they came back without their memories or skills. Now the PCs have to decide what to do- keep on with their current beliefs and behavior, try to run away from the problem, or try to reclaim their "birthright" of being villians. Of course, there is the issue of who brought them back to life in the first place, and why....