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Five years ago, an unexplained accident results in the spread of billions of incomplete microscopic nanites into Earth's atmosphere. The nanites infect all living things and randomly activate, causing some organisms to mutate into Exponentially Variegated Organisms, or EVOs. In response to the Nanite Event, an international organization known as Providence is formed to contain the EVO threat. Rex, a 15-year-old boy, is an amnesiac EVO in Providence's custody who can control nanites, allowing him to both cure some E.V.O.s and manipulate his own nanites to form biomechanical weapons from his body. Under the supervision of Agent Six and Providence head scientist Dr. Rebecca Holiday, Rex deals with E.V.O.s around the world, curing as many as he can. Tiring of Providence's control over his life and poor treatment of him, Rex sneaks out of their headquarters with his EVO chimpanzee friend Bobo and meets Noah Nixon, an ordinary teenage boy whom he befriends.

After Agent Six nearly kills a priest-turned-EVO whom Rex cures at the last moment, Rex becomes conflicted about Providence's ruthless "cure, contain, or kill" policy. Rex, Six, and Bobo are then sent to Manhattan, which has become infested by zombie-like E.V.O.s controlled by an EVO named Peter Meechum. Deeming the spread of Dr.Meechum's control too dangerous to contain, White Knight initiates Bleach Protocol, ordering for a nuclear weapon to be detonated on the Manhattan Bridge to kill Meechum and the infected.

Rex, Noah, and Bobo take a "vacation" to the resort island of Cabo Luna behind Providence's back, where Rex develops a crush on a mysterious girl named Circe. Hearing a strange noise at night, Rex encounters Circe under attack by a huge EVO sea monster. Helping her defeat it, Rex learns that Circe is herself an E.V.O. with the ability to summon other E.V.O.s with a sonic scream, and summoned the sea monster as part of an initiation ritual to join the Pack, the followers of Van Kleiss.

Van Kleiss and the Pack arrive without warning at the Headquarters of the United Nations in New York City, where Rex is forbidden from attacking him due to Van Kleiss possessing diplomatic immunity as the leader of Abysus. Van Kleiss claims he has come to deliver a speech to the United Nations delegates on Abysus' behalf, but Providence remains suspicious of him. Rex is invited to a party by Van Kleiss, which he attends with Six, Bobo, and Holiday.

Rex receives an unexpected phone call from Circe, who claims that there is a problem in Abysus. Rex, Six, Holiday, and Bobo travel to Abysus and find the landscape wasting away, and encounter Circe and the Pack, who explain that Van Kleiss's death has caused the unstable nanite-infused environment of Abysus to come undone. They claim that the only way to reverse the process is via a machine built by Van Kleiss, and Rex reluctantly agrees to help them after Dr. Holiday mentions the risks of allowing the corruption of Abysus to continue. However, Rex backs out after discovering that the machine is designed to resurrect Van Kleiss.

On Rex's "birthday" (the anniversary of when he joined Providence), Agent Six reflects on the day he first met Rex. Years prior, Six and White Knight are partners working for Providence during its early days. During a battle against a gigantic mechanical EVO in Mexico, the EVO explodes and Six discovers a young Rex in its fist. After learning that Rex can cure E.V.O.s, Six secretly brings him to Providence and shows him to then-research assistant Dr. Holiday. White Knight, discovering Rex's nature, orders that he be dissected using a machine that magnetically strips nanites from a host body, killing the host. Six and Knight battle over Rex, and in the process, White is trapped inside of the machine and nearly killed until Rex deactivates it at the last moment.

Van Kleiss and the Pack orchestrate a massive coordinated attack on all major Providence facilities on Earth, with Van Kleiss himself targeting the Keep, the aerial flagship of Providence. Rex, Noah, and Bobo attempt to stop Van Kleiss from taking over the Keep, but Van Kleiss captures Rex, revealing that some of Rex's nanites were left behind when he cured him, giving him knowledge of Rex's abilities. Van Kleiss then steals all of Rex's active nanites, restoring his EVO abilities and leaving Rex powerless. Van Kleiss's lieutenant Biowulf throws Rex out of the Keep, but Rex is narrowly rescued by Holiday. Van Kleiss then discovers that Rex's nanites have given him the ability to turn living things into EVOs, and he proceeds to mutate all of the Keep's crew, including Captain Calan.

Rex is sent on an undercover mission to spy on Van Kleiss and the Pack, including his siren-like sweetheart Circe, who travel to the Bug Jar planning to strike a deal with its leader, NoFace. Rex deviates from the mission in an attempt to bring Circe back to his side; as the two battle, Circe reveals that Van Kleiss wants Rex alive and well, and that there is something about Rex's increasingly powerful new abilities that he still needs.

A mysterious nanite-free zone appears in the midst of a massive storm in the desert. Rex is sent to investigate, discovering that Van Kleiss and the Pack are also present. Rex and Van Kleiss are sucked underground and agree to put aside their differences temporarily to investigate the source of the zone, which Van Kleiss sees as a threat to his EVO existence. As they travel deeper, they realize that their nanites are being slowly destroyed, causing them both to waste away. As they both may perish, Van Kleiss convinces Rex to play a game of quid pro quo for each other's knowledge. Van Kleiss then claims that Caesar was the one responsible for the Nanite Event.

Breach travels to Hong Kong, China, as Van Kleiss has an important mission for her involving Quarry. Worried that she is after Circe, Rex follows her there, but is deeply uncomfortable to see Circe and Skwydd in a supposedly romantic relationship. Elsewhere, Breach springs Quarry out of prison to steal a rare and powerful weapon called a molecular destabilizer.

A scientist named Dr. Brandon Moses allegedly develops a cure for incurable EVOs, which greatly interests Dr. Holiday, who wishes to cure her sister Beverly. Holiday gives Beverly to Moses for him to cure her, but Rex, Six, and Bobo grow suspicious of him. They soon discover that his EVO cure is a ruse, and Moses is in fact collecting dangerous E.V.O.s to sell them to the highest bidder, using a device to supercharge their nanites.

During a battle against Rex, Breach uses a device on her chest to open a portal which releases a Tyrannosaurus rex. Realizing that Van Kleiss has found a way to use Breach's powers to travel through time, Rex decides to bring Breach to Providence's side, and sneaks into Abysus to convince her. Breach reluctantly flees Abysus with Rex, and the two spend time together, with Rex promising nobody at Providence will hurt her. Providence then suddenly arrives and attacks Breach, shortly followed by Van Kleiss, who deactivates Breach's powers. Rex confronts Van Kleiss and apologizes to Breach, demonstrating his trust in her by reactivating her powers.

Rex learns from Black Knight that six months ago, following Rex's disappearance during the incident with Breach, White Knight became erratic and the "Directorate" lost faith in his ability to lead. White Knight then set off bombs in Rex's room, seemingly in an act of suicide. Black Knight attempts to win Rex's trust, showing him how the new Providence has adapted to Rex's absence by developing collars that influence the behaviors of E.V.Os.

A mysterious portal appears above Manhattan and releases sixteen-year-old Benjamin Kirby Tennyson (from Ben 10: Ultimate Alien) into Rex's reality as Humungosaur, whom Rex battles, thinking he is an E.V.O. Meanwhile, a mechanical entity escapes from the portal and attacks Six, placing him in a coma. Rex blames Ben for Six's injury and captures him, but Ben escapes, subsequently realizing that he is no longer in his own world. The two reluctantly agree to help each other just as Caesar arrives. Caesar reveals that the entity that escaped the portal is Alpha, a prototype nanite AI that he developed during the Nanite Project with the intent of enabling nanites to control themselves.

When Alpha became self-aware and attempted to assimilate living things, Caesar developed a device to send it to an empty dimension where it would do no more harm. However, Ben recognizes that Caesar instead sent Alpha to the Null Void, a pocket dimension used as a prison for alien criminals, and was thus responsible for bringing Ben into Rex's universe. Alpha continues to grow in strength by assimilating more living things, until Rex, Ben, and White Knight confront it in the Bug Jar, where it has absorbed all of the resident EVOs. Alpha steals the Omega-1 nanite from Rex, but Ben and Rex work together to remove it, destroying Alpha. Alpha is imprisoned in a dense sphere which Ben brings to the Null Void. Six recovers from his coma, and Rex wonders if he will ever meet Ben again.

Rex, Six, and Bobo travel to Cairo, Egypt, where Dr. Holiday is investigating a recently uncovered ancient tomb containing hieroglyphs seemingly depicting nanites. Black Knight also discovers the tomb, wherein they encounter a mummified pharaoh, Gharun Set, who comes to life. Gharun Set reveals that he is an EVO and was taught English by "the Great Father". Gharun Set escapes from his tomb and reactivates a series of technologically advanced pyramids buried underground, which rise up across Cairo. Gharun Set also destroys the Great Sphinx of Giza, revealed to be a tomb for an enormous two-headed cat EVO which he restores to life.

White Knight reveals intel that Providence is attempting to restart the Nanite Project, for unknown reasons. As a result, Rex and his allies stage an elaborate break-in of the Providence HQ to learn more, but Rex remains adamant that Caesar would never aid in the restoration of the Nanite Project. During the break-in, White Knight reaches his office and retrieves an item from beneath the floor, but Black Knight confronts him, and the two battle. Meanwhile, Rex detours from the plan to speak to Caesar. Caesar states that he is in fact in charge of the new Nanite Project, and is attempting to restore Dr. Gabriel Rylander to life in the same manner as Van Kleiss.

Van Kleiss is revealed to have been sent back in time to the Old Kingdom of Egypt, where he created Gharun Set and the Sphinx, and engineered the technology in the Hall of Records as a means of returning himself to his own time. Van Kleiss is being pursued by a mysterious force, which he is convinced is an "antibody" of spacetime which is attempting to destroy him for being a violation of the laws of physics. Van Kleiss evades the force and places himself within what appears to be a time machine, awakening centuries later in the 2nd century AD, where he is captured by Roman soldiers. Van Kleiss is brought to the Colosseum in Ancient Rome, where he wins the favor of Emperor Septimus Severus, who worships him as a god. Van Kleiss is able to repair his machine and escapes once again as the entity pursues him, jumping across the eras in a desperate effort to make it home.

Black Knight launches an assault on the Providence defectors' base to capture the remaining two Meta-Nanites. During a confrontation with Rex, Black Knight reveals that she herself is an E.V.O. with the same powers as him; she was a test subject during the Nanite Project, and was turned into an E.V.O. after Rex as an "improved version". Providence captures Rex and his team, but Van Kleiss reveals that Rex has the fifth and final Meta-Nanite inside of him, preventing Black Knight from killing him. Rex is transported to the laboratory in Abysus, where Caesar reveals that the only way to safely remove the fifth Meta-Nanite from Rex is to place him inside of the machine that will insert the other four Meta-Nanites into the Consortium. The Consortium and Rex enter the machine - along with Black Knight, who demands the position after threatening the Consortium - resulting in the Meta-Nanites being unexpectedly split between Black Knight and the Consortium members, transforming them into E.V.O.s with mighty reality-warping, elemental and teleporting powers. Angry at the flawed results of the experiment, the Consortium take out their anger on Rex, until Providence suddenly intervenes, with White Knight having returned as leader. Providence evacuates Rex, and they begin plans to fight back against the Consortium.

The Consortium begin to sow chaos across the world, using their powers to pursue personal vendettas and greed. Faced with this threat, Six reveals to Rex the existence of his full bio-mechanical E.V.O. form, which may be powerful enough to stop the Consortium, but could also result in him losing his memories. After contemplating this, Rex finally confronts the Consortium, just as they are attempting to redo the experiment to gain the full power of the Meta-Nanites. Rex enters his full E.V.O. form but is defeated by the Consortium, but retains his memories. The Consortium restart the process, but Van Kleiss betrays them, revealing that he has retained his sanity and has always intended the power of the Meta-Nanites for himself; he strongly implies that he killed Rex's parents after they tried to stop him. Van Kleiss activates the process, but it fails, and his arm is destroyed. Caesar reveals that his late parents secretly programmed the Meta-Nanites to work only for Rex, preventing them from being used by anyone else. Rex absorbs the combined Meta-Nanite and becomes all-powerful. He spontaneously cures every E.V.O. on Earth, then permanently deactivates the Meta-Nanites, not wanting to abuse their power.

A four-part special crossover with Ben 10 (2016–2021), ten-year-old Ben Tennyson meets a ten-year-old Rex, who is on the run with his sidekick monkey Bobo from a hostile Providence working through a series of misunderstandings to battle the magician Hex and save the world from being infected with alien/E.V.O. DNA.

Guest star: Tara Strong as Ben Tennyson