"The fantastic thing about Men in Black 3 is that it totally closes out the trilogy," Sonnenfeld is quoted in the interview. "It answers questions that you didn't even know you should be asking, it leaves you emotionally warm and sad and happy, andit could also reboot the franchise."
The obvious answer, given the time-traveling nature of the series, seems to be that Josh Brolin's Agent K could be shunted forward through time and replace Tommy Lee Jones in future films, although in a stretch the series could stay with him in either the past or present, in an alternate timeline, and leave Will Smith's character in retirement as well.
"Reboot" in either of those scenarios is used loosely, of course--were they to play out, this could be the first film franchise to get the DC Comics treatment--a soft reboot where fans and probably even some characters remember the previous movies.
Men in Black III will be in theaters May 25.