I can, of the top of my head, remember the following games (many of which started on off-the-cuff remarks that grew into a "hey, let's try this for a while" type of campaign):
- Post-holocaust D.I. - After the Plague: a terrible contagion sweeps the world, leaving only -- coincidence of coincidences -- smarter, more motivated, more capable versions of the players themselves as survivors. After rapidly dealing with the emotional trauma of seeing their closest loved ones dead, they begin raiding their homes for supplies and set out to find anyone else who's survived and make a go of it.
- Monster Fighters D.I.: mildly super-powered versions of the players (think of the slightly more useful members of the Legion of Substitute Heroes) encounter the world of vampires, werewolves, and other creatures of the night and must endure a life on the run while seeking out their shadowy archnemesis in a bid to end his reign of terror.
- They Live Among Us D.I.: the PCs, normal people with regular jobs, stumble onto an alien conspiracy and are forced to leave their lives behind. They fight against strange creatures, try to find other people who know, and desperately seek a way to fight back against these strange alien oppressors.
- Post-holocaust D.I. - Zombies: much like the other post-holocaust D.I., only with the now, very much popular zombie apocalypse in effect.
- Team Looney Tunes D.I.: a crack special operations unit is sent out to resolve matters that would normally qualify as X-file material: a monster claiming the lives of an isolated Arctic research station; a preternaturally strong humanoid predator lurking in the sewers; a paramilitary cult in the wilds of Africa rumored to have mystical powers. Each team member was code-named after a Looney Tune -- only Bugs Bunny was off-limits. He was James Bond meets Jason from Friday the 13th, called in only when the team couldn't resolve matters.
Yes, it was the Hero System, but before 4th edition, when they really started pushing the system as the core brand rather than a unifying brand across RPGs. And we'd already been shuffling rules around the various Hero RPGs anyway. And it was a lot of fun.
Too bad none of them lasted more than a year. But at least we have the memories, the variety, and the option to go back to the well some time in the future.