Due to the line of Kree Sentries - alien robots that have been observing the Fantastic Four - having been destroyed, Johnny is put on trial by Ronan the Accuser against the Kree Empire. Ben and Susan are set to defend him, and Reed is chosen as his lawyer. However, since Johnny is already presumed guilty before the trial starts, it's not going to be easy.
Dr. Doom manages to transfer his mind into Reed's body by hacking his consciousness. Reed, who is now trapped in Dr. Doom's body, must now figure out a way to return to his friends and family, or else Dr. Doom will destroy the Fantastic Four and several city blocks by transforming the Baxter Building into his new weapon.
Reed stands accused of purposefully exposing Susan, Johnny and Ben to the cosmic rays that have transformed them into the Fantastic Four. While they're distracted by this turmoil, Dr. Doom strikes!
Fellow scientist and friend Bruce Banner comes to Reed looking for help. But his dark secret is soon revealed - he's the Incredible Hulk! When Banner reverts to his giant green alter-ego and goes on a rampage across New York City, the Fantastic Four must stop him.
Upon returning from a mission, the team finds their neighbors in the Baxter Building much more friendly than usual, but it soon becomes clear their "neighbors" are shape-shifting aliens - the Skrulls!
Reed's miniaturization experiment malfunctions, shrinking the team and putting them at risk when H.E.R.B.I.E. incorrectly identifies them as vermin and tries to exterminate them.
Things take a turn for the worse when Johnny gives his friend Frankie an unauthorized tour of Reed's lab. When Frankie is sucked into another dimension, Johnny goes in after her to prevent anyone from finding out. But as he does so, a small bug comes through the dimensional portal. Susan, Ben, and Reed now have to deal with the bug, while Frankie and Johnny are trapped in the other dimension.
Namor the Sub-Mariner arrives with a decree banning humankind from the oceans. Susan and Johnny go underwater to negotiate, but are taken prisoner in Atlantis. Ben and Reed must fight their way through sea monsters and Namor to save their teammates.
Alicia's stepfather and artist, Phillip, gets hold of a piece of the Reed's space station and the irradiated metal gives him the ability to control the minds of others through miniature clay statues.
When Reed recall one of his deep-space probes, it brings back with it the Impossible Man. The Fantastic Four must find a way to get rid of the annoying imp before his antics become dangerous.
Dr. Doom causes an energy surge during one of Reed's experiments. As a result the Four have swapped powers with one another. Now the team must face Doom with new and untrained skills.
The Fantastic Four are brought to the Negative Zone where they come face to face with Annihilus. As if that wasn't bad enough, Dr. Doom arrives stealing Annihilus' power source and threatening Earth.
The Mole Man sends a giant monster to attack the Baxter Building, hoping to lure the Fantastic Four into his kingdom of Subterranea.
The Four have a contest called "Fantastic Fifth for a Day." But when the Skrulls return with the Super Skrull, it may be up to nerdy teen Rupert, the Fantastic Fifth, to save the day.
The Mole Man is back. After kidnapping Ben, Mole Man attempts to get the Thing to join forces with him to create an underground paradise where appearances don't matter.
The Puppet Master gets the city to turn on the Fantastic Four. The Four must clear their good names and stop the Puppet Master from taking over the minds of everyone on Earth.
Doombots invade the Baxter Building in the middle of the night, but their attack is just a distraction for Doom to launch the Baxter Building into space.
Reed finally cures the Thing, but the cure also takes away all of his memories since the formation of the Fantastic Four. When the Mole Man attacks, She-Hulk must fill in for the Thing while the powerless Ben Grimm must find a way to save the day.
The Wizard, Klaw, Trapster, and Dragon Man are the new team in town saving New York always one step ahead of the Fantastic Four. Reed begins to suspects that these Frightful Four are not the heroes they appear to be.
The Fantastic Four return to New York to find that Doom has taken over the city and due to a change in history, they never got their powers. The Four must go back in time to set things right and to stop Doom.
The Sub-Mariner returns, but this time he needs help to defeat Attuma, who has taken over Atlantis. While Reed, Susan, and Ben head off to help free Atlantis, Johnny stays behind and faces an attack on the city from a giant mutant whale.
After several attacks from Iron Man suits, the Fantastic Four track down Tony Stark. It turns out Doom was behind the attacks, and now the Four have to face both Iron Doom and Iron Man under Doom's control.
During a confrontation with Diablo, Johnny is exposed to a potion that makes him more powerful. Unfortunately, the potion also begins to turn him evil.
The Grandmaster forces the Fantastic Four to battle Ronan the Accuser, Impossible Man, Annihilus, and Super Skrull. The fate of humanity depends on the winners of this mighty contest.
Doctor Doom creates a super Doombot to face the Fantastic Four. The Four try and retrain this robot to be one of the good guys, but Doom's control is too strong and Doom captures Susan and Reed. Johnny and Ben must fight Doom, but they have to get through the super Doombot first.
Terminus, an alien scavenger, comes to steal all of Earth's resources. While the Fantastic Four try to stop him, they realize he may be unbeatable.
