In the year 2099, Mister Fantastic, the Invisible Woman, the Human Torch, and the Thing found themselves in new uniforms and transported to a very different Negative Zone than the one they knew. Returning home, they fond the world changed and SHIELD soldiers chasing after them as laboratory copies of the original Fantastic Four.
During a fight with a repo-man crew named Total Recall, a church dedicated to the worship of the 20th century’s Thor was destroyed, and the FF escaped with an injured Human Torch to an abandoned S.H.I.E.L.D. hideout. They discovered, through the repo-men, that the corporation Stark-Fujikawa was claiming them as "experimental subjects". They headed to an Alchemax facility to prove their originality. The four encountered the new century's Spider-Man. He helped Reed study the group's DNA. Unfortunately, due to the nature of the 2099 technology, the results were inconclusive, leaving their legitimacy in question.
They then broke into their old headquarters at Four Freedoms Plaza with the help of their friend, Chimera, who came back with them from the Negative Zone. Before they could return to the Negative Zone to find a way home, they were attacked by a man named River Styx, the demon brother of Chimera, as well as a group of S.H.I.E.L.D. soldiers. In the course of the battle, the Negative Zone door was damaged, causing a dimensional 'meltdown'. Rampaging beasts called Mindless Ones attacked, until they were destroyed by the 20th century's Doctor Strange. Strange then leapt into the future to warn the denizens of Earth of the approaching end of the world.
Later, a planetoid headed to Earth, causing the polar ice caps to melt. This was caused by the Phalanx, an act which covered most of the Earth in water. The Fantastic Four set up headquarters in their old building to help the Earth’s future inhabitants. The Human Torch headed out to investigate the flooding, but was ambushed and captured by the Atlanteans and their leader, Attuma. The Invisible Woman and the Thing rushed to his rescue, getting themselves captured as well. They found themselves caught in the middle of a fight between Attuma and the rightful ruler of Atlantis, the mutant Whisper, a former guardian of X-Nation. Despite chemical brainwashing, the three heroes helped Whisper take her rightful place on the throne.
Back in the city, Reed and the future Doctor Doom worked with the remaining survivors. While fleeing the city towards the Savage Land, the only place on Earth free from flooding, a fleet of Atlantean ships attacked the remaining humans. The human fleet was saved from destruction by the interference of Doom's Latverian Luftwaffe, and finally by Whisper, as she asserted her newfound control.
The Fantastic Four, along with the last refugees of Earth, finally settled in the Savage Land to rebuild humanity. Their next step was to send out a ship piloted by the Thing, and crewed by Father Jennifer and the mutants December, Twilight, and Metalsmith. The goal was to rendezvous with the human colony on Mars, in order to establish relations and ask for help. Cosmic rays caused the ship to crash.
Back on Earth, Johnny and Susan despaired as Reed drove himself to exhaustion to establish a technological infrastructure for the remaining humans. All three grieved for Ben's presumed loss, but Reed took it the worst, actually hallucinating at one point that Metalhead was Ben.
Sue and Johnny confronted Reed, who stated his intention to stay in the 2099 era. They left him behind. Reed accomplished his goal, making a repository of knowledge for the last of humanity. Shocked back to sanity by the databank's physical resemblance to his son Franklin, Reed raced back to Four Freedoms Plaza just in time to join Johnny and Sue. They vanished into the Negative Zone, destination uncertain.
The mutants later return to Earth with Martian aliens and resources in an attempt to help the survivors.
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