Apocalypse resurfaced in the early twenty-first century, bringing with him his endgame, the Great Trials. Entire civilizations and races were wiped out in its wake, and the only survivors - the Atlanteans, the Inhumans, the Stark-Self, the Wakandans, the Mystics, and the Moloids - lived under his rule in Omega World, a vast structure where what remained of Earth was kept. While Apocalypse became the heart of Omega World, turning the whole structure into his body, his Horsemen started to function as his antibodies, cleansing Omega World of anything that could do him harm.
When Colossus and the team of young Mutants under his care were accidentally teleported from the past to Omega World by the Sugar Man's time-machine, Apocalypse's Horsemen attacked them, but only Colossus was subdued as he held the Horsemen off long enough for the others to escape. After converting Colossus into one of his Horsemen, Apocalypse ordered them to retrieve the ark in possession of the young X-Men, which contained six hundred mutant embryos. However, as they were always on the move, his Horsemen always lost track of them.
One year later, Storm and the other X-Men, who had just arrived to rescue Colossus and his team, found the young Mutants in the Moloids territory, and so did Apocalypse's Horsemen. After the Horsemen successfully retrieved the ark, Apocalypse had it destroyed.
While his Horsemen fought the X-Men, Apocalypse battled their leader, Storm, and ended up being stabbed in the back by a furious Nightcrawler, who had discovered Apocalypse destroyed the ark. With Apocalypse fatally wounded, Omega World started to crumble. After being rescued from certain death by the X-Men and taken to the past to escape Omega World's destruction as well as to transform Colossus back to normal, Apocalypse teleported Colossus away, sending him to Clan Akkaba.
Apocalypse was kept at X-Haven, inside a cell specially built to contain him by Forge, who tried to find a way to cure Colossus by reverse engineering Apocalypse's powers but failed. During the World-Eater's attack on Limbo, Nightcrawler accepted to free Apocalypse in exchange for a cure for his friend. What Apocalypse did not expect was that Nightcrawler would throw him into the vortex created by the World-Eater to consume Limbo, seemingly killing him.
- 6 Appearances of En Sabah Nur (Earth-16558)
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