Casey Hudson, Creative Director for BioWare, has told OXM that Mass Effect 3's epic finale will make things challenging for the team for future Mass Effect titles (Mass Effect 4 already?):
I think with each game we throw forward a few threads, so we know where we're going, we have lifelines to hang onto. But with everything else we went right ahead and made things difficult for ourselves! And even more so for this.
We want to end the trilogy really strongly, and that's the most important thing, and then we have a few ideas for things we can think about doing in the future. But we're okay with making it difficult for ourselves, because the most important thing is giving people a great ending.
We want to do more stuff with Mass Effect, of course, and I'm sure we will. But we're not really thinking about that right now. We want to make sure we give people the best ending to Mass Effect 3 that we can.
And we have an idea of how to do that - let people have the maximum impact and the maximum fun with this playground. We've always envisaged this as three really good games, and this one is the story of all-out galactic war.
This supports the idea that the would-be Mass Effect 4 will likely take place after the events in Mass Effect 3, though I am devilishly interested in the struggles on Earth during first contact with the Turians. The Mass Effect origin story is one I want told. But either way, I'll be happy with more Mass Effect.