While there are some debates, D2R Ladder still has its place within the larger Diablo narrative. After the events in the D2R Items: Lord of Destruction expansion, and prior to the launch Diablo 3. Diablo 3. D2R Ladder is set following the fight against Baal during the battle at the Worldstone Keep. With Baal defeated and the Worldstone Keep destroyed, the Archangel Tyrael has no choice but to take down the Worldstone as it had been corrupted by nefarious Prime Evil during 1265. and the Worldstone was destroyed, and littered across the land. Diablo 3 takes place twenty years later in 1285. when the consequences of this massive action begin to be felt However, players will be able to see what happens to the fragments in D2R Ladder.

Set in 1270. just five years after Tyrael's the drastic choice to destroy the tainted Worldstone, Diablo D2R Ladder shows how the fragments that have been corrupted remain dormant and that more than a few of the demons in the world would have no problem taking them. With the Lord of Terror's Soulstone destroyed at the Hellforgein Diablo's loyal followers want to gather the fragments of the Worldstone to once again bring him back to usher in the reign of destruction and chaos. During D2R Ladder it is assumed that Tyrael is dead following the battle that ended at the end in Diablo 2. and Sanctuary is again facing an uncertain fate as an arena of battle for the forces of evil and good.

The mission of the game is to find and destroy the fragments of the broken Worldstone by fan-favorite NPC Deckard Cain prior to when they can be used to trigger catastrophic events, players must explore the landscape as they deal with the consequences of Tyrael's action. The fragments of Worldstone have also drawn the attention of other ancient evils such as Skarn one of the gods of Damnation who wants to get the pieces in order to utilize their power to oppress humanity.

Because D2R Ladder's role is the sequel to buy d2r items and a prequel to Diablo 3. it occupies an intriguing position in the chronology. As an MMORPG the game will receive continual updates and new content over a number of years, and will also include expansions to the story that will eventually take in the entire gap in time in between Diablo 2 in 1265 and Diablo 3 in 1285.