Not long ago there was a thread in this forum which discussed this very topic. There were some nice ideas in it (I even posted one myself). Sadly it seems to have vanished.
I know, it pisses me off that threads on this particular board seem to be purged so quickly.
It's important for any sci-fi to have issues that deal with current events. I think a cool idea would be a Trek set in the future beyond Nemesis (maybe 25-30 years ahead) that involves more exploration (beyond Cardassia into other parts of the Alpha quadrant, and perhaps more Gamma quadrant), set on the Enterprise-F. The Federation is aging a bit and resources like dilithium are starting to become more scarce.
A terrorist event occurs on a planet that joined the Federation during the Dominion war. The planet, as well as a number of nearby related star systems, were swiftly accepted into the Federation so that they could contribute to the war effort (keeping in mind that, at times, victory looked nearly impossible, creating this urgency). 25+ years since then their differences become a major issue with this terrorist attack, and suddenly the Enterprise has to play a peacekeeping role (a diplomatic legacy left by Picard).
Anyways, I've thought a lot about this idea and could type pages and pages (I have a crew, pilot outline, and series arc), but I'll leave it at that for now. Summary: 25+ years after Nemesis, Enterprise-F, exploration, civil unrest.