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Nathaniel Essex was a biologist in Victorian England who developed advanced theories on human evolution. A geneticist of unparalleled genius, he foresaw the coming mutations that would transform mankind. However, his unorthodox experiments resulted in his ouster from the Royal Society and caused his wife to shun him. These rejections led him to ally himself with Apocalypse, an immortal mutant who has witnessed virtually the whole of human history. Apocalypse transformed Essex into the ageless being known as Mr. Sinister.

Sinister has conducted numerous experiments in his time. He operated an obstetrics clinic in New York in the late 19th century and performed side research on society's deviants. As Dr. Essex, he influenced the work of Herbert Wyndham, the man who became the High Evolutionary.

Sinister plotted the course of certain gene pools for more than a century, discovering that the combination of Scott Summers' and Jean Grey's traits would produce a mutant of incredible power. The future Cyclops was brought to Sinister's orphanage in Nebraska, and the geneticist collected a blood sample from the girl who would come to be known as Phoenix to confirm his findings. Sinister used that sample when Jean died to create a clone, Madelyne Pryor, who later became the evil Goblin Queen.

Following up on his genetic pursuits, Sinister set in motion the so-called "Mutant Massacre." A community of mutants who considered themselves outcasts from society, the Morlocks lived in tunnels under New York City. Sinister's Marauders annihilated the Morlocks because he considered them genetically useless.

Sinister first fought the X-Men during the "Inferno" crisis, an invasion of demon mutants he helped create. He sometimes aids Charles Xavier's team, but for his own reasons. Sinister helped Gambit save the savage Sabretooth's life, and assisted the X-Man again when he became trapped in the 19th century; took in the mutant Threnody and provided her with devices to control her energy releases; and returned Courier, a messenger with the ability to control every molecule in his body, to a more human state. In almost every case, however, Sinister exacts a price very costly to the soul.

When the High Evolutionary activated a satellite that stripped all Homo superior of their mutations, Essex, who had come to support his student's work, revealed himself as Sinister and modified the beam to mutate every human on Earth, hoping to create an entire planet of lab subjects. Soon after, the mysterious Neo attacked many of Sinister's facilities.