Bioware har tidligere fortalt hvordan Shepard's rejse i Mass Effect-universet indtil videre er afsluttet, og at det kommende Mass Effect 4 derfor vil fortælle en helt ny historie.
Det bliver nu igen bekræftet af Biowares Mac Walters, der til dagligt arbejder som hovedforfatter på spillet. I et interview med Complex lyder det således:
"Well, I can't get into details, but the idea is that we have agreed to tell a story that doesn't relate necessarily to any of the Shepard events at all, whatsoever. Beyond that, that's what we've been deciding for awhile. But throughout it all, one of the key things is that it has to be Mass Effect. It can't just feel like a spin-off. It has to feel like a Mass Effect game at its heart, at its core. Just without the Shepard character or the Shepard specific companions."