Diablo, imbued with the essences of all seven Prime Evils of the Burning Hells, was defeated by the Nephalem.
The leader of the Angiris Council, imbued with the powers of death and the Prime Evils, was defeated by the Nephalem.
The Nephalem's personal thoughts as they go to confront Malthael (What's interesting is that Malthael's plan would have ultimately failed since eliminating all the demons/evil in the universe would have upset the Balance. "Good must always outshine Evil, but never should Evil be completely eradicated, lest Good eventually turn on itself.") hint towards what may come. "It is past time for us to say "No more." The days of angels and demons threatening the existence of our world must end."
At the end, Tyrael is also worried that the Nephalem hero is susceptible to corruption, and that he may be 'our' aka the angels' doom.
We know we are at the final line of the Prophecy of the End Days (The 'Death, at last, shall spread its wings over all' line was used during RoS' advertising), or at least the final line as portrayed in the Book of Cain: "As Fate lies shattered forever." Everything else is talking about one of the angelic Aspects, so Fate should mean Ithereal, but we also know that the Nephalem are not part of the Scroll of Fate and at the end of RoS are fed up with being harassed and murdered by the angels and demons, so that could be used to shatter the 'fate' of demons and angels endlessly fighting. (One thing to note though is that they may've gone 'off the rails' storywise as the RoS behind the Scenes says Valor aka Imperius was very much supposed to go Wrath since he was the primary antagonist originally and was supposed to kill or gravely injure the mortal Tyrael, which very well might have started the End of Days since Tyrael claimed Wisdom, which is 'lost' at the start of the prophecy.)
So, there's a couple things I can see them doing from what they've got set up:
Diablo becomes Tathamet again as the 'endgame' for the trilogy's storyline, which they said would be resolved in Diablo 3 (but not the end of the Diablo series). This is hinted at in a conversation with Tyrael, and seemingly is one of the few ways to make Diablo a threat again. We also know he's definitely not out of the fight yet, since he had a vision he shared with Adria that you would be responsible for freeing him again, technically it was Malthael but we were the cause.
The Final Battle/End Days that have been hinted at since Diablo II finally happens. "The Prophecy of the End Days is contained within the Horadric tomes I inherited from my ancestor Jered Cain. It is a warning to those who could interpret it regarding Hell's ultimate invasion of our world, written by many different people throughout history in many different lands."
'At the End of Days, angels and demons fight on the land of man.' This was said in the Behind the Scenes DVD from the base game, and I'm sure the majority of us thought it meant the angels would be fighting against the demons. Well, now that the Nephalem have firmly cemented themselves as an enormous threat to both sides, perhaps the angels and demons do indeed fight on the land of man, but in an unthinkable alliance against the mortal threat since they share a common goal. We are told that Imperius controls the angelic host, so if that scenario did happen it has to be by his command, unless it's a splinter group of angels like the minions of Malthael. (On the other hand, this bit of the prophecy could have been fulfilled already by Belial/Azmodan's forces and then Malthael's forces invading Sanctuary)
Gods such as Dirgest may get involved, possibly to do the same as the Zoltun Kulle/Lilith scenario. I don't think we really know what 'gods' are in the Diablo universe, some seem to refer to Nephalem of old, the Monks' are the angels/demons I think, there's the 59 gods of the Xiansai, Dirgest the god of desire, etc. Whatever they are, they are likely powerful and based on Sanctuary, so if angels/demons are trying to destroy it (and assuming all gods aren't angels/demons), they could work to intervene.
Trag'Oul, the guardian of Sanctuary, the maintainer of the Balance, founded the Priests of Rathma aka Necromancers and disappeared. Will he return now that the Balance has been upset by Malthael's actions? (as evidenced by Necromancer NPCs in Act V trying to restore it)