I've been contemplating setting my next Trek game (which might not be for a few months owing to a little movie coming out this summer with Jedi Knights and stuff...) during the time period of "Enterprise". Just sort of an idea right now, but anyways...
One thing which is obviously an obstacle is the fact that all it takes is one episode from Paramount to totally destroy major campaign assumptions. For example, set the game on NX-02 which you name Challenger only to see a Lexington as NX-02 after playing for five months. Put a Tellarite on an early Federation ship only to discover that the Tellarites weren't founding members of the Federation - indeed, they wind up being at war with the early Federation...
Obviously it's the group's game, but I always prefer sticking to the shows where possible. So what follows are random ramblings while I wait for a build to finish at work...
Time - While it is very tempting to set a game right after the founding of the Federation, that period is so unknown that "Enterprise" might do something big to contradict assumptions made abou the early Federation. So it would seem best to make the game concurrent with "Enterprise" - maybe start it early in season 1 - I'm thinking just after "The Andorian Incident" to allow the use of Andorians in the game.
Ship - I like the Enterprise but it occurs it might be better to use a different type of ship to avoid contradicting what "Enterprise" says about other NX ships. The Daedalus is also tempting, but it might become invented in the course of the show. So inventing a new ship seems a good way to go. I'd say take an older ship and say she was refitted with similar Warp 5 engines like "Entrerprise" has. I notice that there seems to be a tendency of older Earth ships to look like rockets - Phoenix, Valiant, those funky ships during the credits, etc. so it might be neat to change the orientation of the ship to be vertical instead of horizontal - i.e. instead of flying "forward" the ship would be flying "up". This is a great excuse to steal deckplans from the defunct Star Frontiers and Buck Rogers: XXVc roleplaying games.
Tech - The tech of NX-01 Enterprise would represent an upper boundary. I'd actually go a little lower tech - perhaps no transporter at all, or one just not plain safe at all for living beings. Also, it might be neat to not outfit the ship with phase pistols, instead using lasers as indicated in Coda Trek.
Player Characters - Earth Starfleet by default. However, there is room for other species. Vulcans are obvious - another liason officer like T'Pol. And it makes for a good chance to play a butt-headed Vulcan.Indeed, this is a great opportunity for non-Starfleet types, as humans seem strarved for guides. You could have a member of an alien species which just likes cruising the galaxy and thinks it'd be fun to hang out with these humans for a while. Other than Vulcans, the known Trek races may be a little dangerous. Orions are probably safe, since I have a hunch we won't be seeing them on Enterprise, though that is just a hunch. An Andorian could be very interesting, but also dangerous - there is sure to be more information regarding them as the show progresses. Klingons should probably be avoided.
Bad Guys - Klingons make for great "space vikings". Andorian and Vulcan ships would make for good adversaries.
Misison - Obviously to explore.I'd lean towards having the ship fly in the opposite direction of Enterprise and tend to avoid first contacts with species that appear in later shows since "Enterprise" will most likely do that. So a lot of species to invent. Also, conflict with Boomers, Nausicaan Pirates, Klingon Raiders, etc. all make for good additions to adventures.
Just a few ideas. Others feel free to chime in.