Van Kleiss is the primary antagonist of the series. Van Kleiss appears to know quite a bit about Rex, and knows what caused the nanite incident. He saw the nanite incident as the dawn of a new age for humanity, and seeks to create a world populated entirely by E.V.O.s. Like Rex, he is able to control his nanites; unlike Rex however, his mutation is unstable and requires a constant supply of fresh nanites, extracted from other E.V.O.s, who are petrified in the process. He does this with needles on his gauntlet that go into the E.V.O. With his E.V.O. enforcers, the Pack, he has established a domain called Abysus at the original site of the nanite explosion, and has seeded nanites for miles in the area. As a result, he can control everything in his sphere of influence, and even regenerate completely from the ground if his body is destroyed. He has a highly extensive knowledge of the nanites, having apparently worked on or been familiar with the experiment which released them, and about Rex's past. He is killed in "Dark Passage" while attempting to secure Dr. Gabriel Rylander's nanite laboratory, but is resurrected in "What Lies Beneath" by his followers and Rex, to prevent Abysus from becoming unstable. Rex cures him shortly thereafter. In doing so however, he gives Van Kleiss the means to study his nanites, which Van Kleiss then uses to gain the power to create E.V.O.s by touch, leaving a handprint-mark. E.V.O.s created by Van Kleiss are extremely unstable, meaning that the transformation becomes permanent if not cured within a time limit. Curiously in the first season finale "Payback" when Van Kleiss drained Rex of his active nanites, Rex wasn't petrified. This was most likely because Van Kleiss was not able to absorb the Omega-One nanite that Dr. Rylander had injected into Rex, thus protecting him from becoming petrified like Van Kleiss' other victims. In "Lions and Lambs," Van Kleiss attaches a device to Breach in a plot to travel through time. When Breach ends up sending Van Kleiss away in a bright golden-colored time portal, Breach starts to disappear as Rex is mysteriously transported six months into the future where Providence is run by a woman called Black Knight. In "A Brief History of Time," it is later revealed that Van Kleiss was sent 4000 years into the past and began working to return to the present all the while pursued by an unknown entity that he believed sought to destroy him. His journey took him through multiple eras, such as the Roman Empire (during the reign of Septimius Severus) and an unknown Japanese era. When he is found by Rex and Providence, he has grown a beard and seemingly been driven to the brink of insanity by his ordeal. He was knocked out by Bobo Haha and taken away by Providence. He also has unknown connections with Black Knight when she appeared where Van Kleiss was placed. In "End Game" Pt. 2, during the final cure, he is dragged by Breach into one of her wormholes. His fate is unknown. The name Van Kleiss is Dutch for "Of This Earth," which could be a reference to his original nature/earth-controlling abilities.

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