Here's one for you; we are now further from The Simpsons Movie than The Simpsons Movie was from good Simpsons. It came out a full decade ago and is still remarkable for not being total bullplop, evidenced by the constant question of whether we'll eventually see a sequel. The latest word is "if we get a good enough script", which is almost as non-committal as Marge's worried grunt (and nowhere near as reassuring).
At this point, it'd be hard for The Simpsons Movie 2 (The Simpsons Sequel?) to not wind up coming at the latter end of the show's run, so why not embrace that and make it the very end.
In terms of plot, this would need to be something that honours the show's whole run and acts as an actual end-point (so could crib from any of the other suggestions on this list), but the event alone would make it noteworthy. Maybe get the likes of Conan O'Brien and Bill Oakley to come back in advisor roles to really get the hype going and you have a trillion dollar bill in the making.