The Soulstone shatters in the bottom of the Abyss, releasing the Lords and their various other minions.
Magda dies a horrible, horrible death.
Demons that were once dead begin to swarm out of the Abyss into Sanctuary (Hello, Andariel! We all love you!) and you are called upon to stop them. Now it's a race to see who can reach the Rift between Sanc. and the Abyss. If you lose, Diablo and Co. get free reign over Sanctuary.
The Templar and the Enchantress die horrible, horrible deaths.
Heaven, although rebuilt, is crippled; over half the angels are dead and the Crystal thingy that acts as their Abyss is cracked, leading to their extremely slow resurrection. The remaining High Council begins to feud over the problem of the emerging Nephelam, and a civil war begins to spark amid the surviving angels.
Hell is left completely empty (since, you know, you killed everyone. Somehow.) The mad heres from 20 years ago are led into the Burning Hells by an old woman claiming to be the wife of Terror. These fallen heroes are assaulted by the temptation of Hell and are slowly twisted into new Lords of Hell to lead a new assault on Heaven while it is weak.
In Sanctuary itself, the rulers of the various kingdoms are arguing over the return of the Nephlam as well. Some kings think they will bring peace and plenty to their lands. Others think the Nephlam seek to sieze their seats of power. Two factions gradually form, and a civil war begins to consume Sanctuary.