There's been talk lately (starting here and spreading elsewhere) about the "dungeon only" campaign, where there is one large dungeon (presumably a megadungeon) and little development of anything outside it.
Except that when I saw that post, I immediately thought of a campaign that starts and stays within a dungeon. Sort of like the kingdom of Zork, or maybe a medieval equivalent of Cleopatra 2525, where everyone lives underground to avoid attacks from dangerous alien/robots.
If you started the campaign in a sprawling, multi-level dungeon, with mostly abandoned "wilderness/ruins" levels above and strange dark things below your underground colony, you could create a very claustrophobic, controlled setting with lots of mystery. Why are they living underground? How far up is it to the outer world? What's up there? Are there any other civilizations, above or below ground? All of these could be discovered through exploration.
I see this as working a little like the world ship in Metamorphosis: Alpha. In fact, for all the players know, they may be *on* a world ship. You could have the same kind of post-apocalyptic inside jokes you see in Thundarr the Barbarian and similar settings, where the characters don't know the significance of the things they find, but the players know they are references to the familiar things of our own world.