I'm tempted to start a new, MASSIVE game (5k+ systems, possibly with 2 galaxies with far larger than default spacing. This would also mean I would most likely use Galactic Armory) against 5 or more AI on the hardest difficulty (random). Research, resource, and other rates that would just get crazy after such a long game on default would be turned down so as to minimize calculations and to make it more difficult to get god-mode ships, ringworlds, and other end-game items. For example, I would turn research way down so no one gets the jump drive (henceforth 'hyperdrive') 20 minutes in - that should be at least 5 hours from start. I'm trying to give it the feel so that at start, it feels like it is maybe 2050 when interplanetary (not other systems!) colonization may be possible if the entire planet worked toward it. It (likely) wouldn't be for several hundred years until an actual hyperdrive is developed.
Would anyone be interested in hearing a story about the progression of a game such as this (from an in-game race point of view, not my own out-of-game, although I would update with statistics and such throughout). If so, feel free to submit ideas to make this game more interesting, challenging, or otherwise different.
So, summary of what I have so far: 5,000+ systems. 1-2 galaxies. Higher than default spacing (thinking 500+ AU after reading Ibanix's thread). At LEAST 4-5 AI of the Hardest difficulty, set to Random perk. A story will be told from my race's point of view on their expansion throughout the galaxy.