With many of the central X-Men gone (Scott, Jean, Xavier) and with the difficulty of re-hiring such celebrity actors such as Halle Berry and Hugh Jackman to return the best possible situation would be to produce a "New Mutants"-esque film with Iceman, Colossus, Kitty Pryde, Angel, etc. taking over as the main X-Men many years after the events of The Last Stand.
You could have Beast remain as Headmaster, and even possibly reintroduce Nightcrawler. It would also give the option to feature new X-kids from the comics (such as Cannonball, Sage, Sunspot, Karma, Psyche, etc.) and concurrently bring old favorites into the mix (Gambit, Havoc, Banshee, Bishop, et al).
As for villains, I think Apocalypse and/or Mr. Sinister could be done adequately in a cinematic format. And then there's always the Hellfire Club, the Morlocks, the Hellions and so forth.
I'd like to see a new generation of X-Men, instead of feeling compelled to stick to the old. X-Men's expansive history lends itself towards many incarnations, intrepretations, characters and storylines and there's a plethora of possibilities to choose them.