I figured a new bad guy needs to show up: the Kelinan or some other race.
The UFP took a serious hit with Borg and Dominion War, but for me the betrayal of their ideals -- working with the So'na, the attempt to move the Ba'ku, dirty tricks by Section 31 -- all weakened the faith of some of the newer member races. I see a bunch of little worlds pulling out of the Federation, but ultimately, it stabilizes and comes back. I see Bajor winding up as a major player in the UFP.
The Cardassian Union is broken by the war and never really recovers. I see them going through a period of balkanization and warlordism that makes diplomacy with them near impossible. Everytime they start to get somewhere, a new warlord pops up and screws the whole thing up.
The Ferengi start to move toward the UFP, but the Grand Nagus is knocked off by free trade factions and they ally themselves heavily with the Orions. I would have the Orions as an up-and-coming power -- still decadent, but pulling themselves into a more cohesive confederation with other minor powers looking to not get swallowed up by any of the bigger powers.
The Romulans: I had them fight a civil war between the Tal Shiar-imperialist faction and the more open pro-Vulcan/UFP faction. Lead by one of the commanders of the Romulan forces in the DW, the latter forces win, but the nw relations are uneasy and are causing distrust of the VUlcans in some camps of the UFP. This could all be a very clever trick to lower the Fed's guard, after all...
The Klingons: another civil war, sparked off by the Romulan-UFP relations and Martok is toppled for a more nationalist Klingon faction. They haven't gone to war with the Federation, but they are repudiating certain treaties that they feel weaken them. Lots of cold war stuff between the Klingns and Romulans over who 'gets to have' the Federation as friends.
The Dominion. You can always bring them back. Great villains.
The Borg. If you use Voyager in your game canon, I'd just leave them out -- they were emasculated before the horrible end episode.
Androids. Daystroms cracked the problem. They're a burgeoning section of the population. Not all are humanoid in form, there are robots and sentient starships. Machine intelligence is getting frighteningly smart and adaptive...
Slipstream travel is becoming the norm, with warp as backup. Transwarp, slower than the slipstream, is now a dead line of technology.
Genetic engineering: making a comeback. Some of the problems of early eugenics programs have been hammered out. Still unpopular in the Federation, but increasingly used in other cultures.
Nanotechnology: better, faster, and gives you cool toys like the Batman armor from the last Voyager episode. Nano-based robotics allow for androids that can change appearance and have a lot of the same qualities as holography, but more stable.
Medical tech: death? What's that?
"War is an ugly thing but not the ugliest of things; the decayed and degraded state of moral and patriotic feelings which thinks that nothing is worth war is much worse. A man who has nothing for which he is willing to fight, nothing which is more important than his own personal safety, is a miserable creature and has no chance of being free unless made and kept so by the exertions of better men than himself."
John Stuart Mill