My ultimate game is one that has been rattling around in my brain for years. It would be set in an underground lab and you would start off my creating a very simple monster that would begin life in an incubation tube.
You would choose from a list of basic abilities and would be assigned a random weakness and try to escape the lab. Every time I see a monster in a movie that is just human science gone wrong, I always sympathize with the monster. People made it that way, then they keep it locked up and experiment on it!
I would love if the game would start off small, being played mostly as a sneaking game, and end up a huge city-levelling Godzilla romp.