During the 19th Century, Nathaniel Essex encountered Apocalypse who used his technology to transform Essex into “Sinister”, the last word his dying wife ever spoke to him.

Soon after, a time displaced Gambit and Courier approached Sinister for help. Sinister agreed to help them, as long as he could have a DNA sample from Courier. This DNA sample allowed Sinister to replicate Courier shape shifting abilities, within Sinister’s own body.

By the early 20th Century, Sinister had cracked the genetic genome and was willing to share the information with Herbert Edgar Wyndham, who would later become the High Evolutionary.

During World War II, Sinister worked alongside the Nazis, collecting as many blood samples as he could. It was during this time that he first saw Sub-Mariner, and was inspired to create a clone of Namor. The clone was experiment N2 and had varied success against the original Namor but was defeated by Captain America.

Some time later, Sinister recruited Gambit to gather together the Marauders and ordered the massacre of the Morlocks. Sinister cloned Jean Grey in the form of Madelyne Pryor, so that Cyclops would have a child with her, which Sinister would view as the ultimate mutant. Ultimately, Cyclops rejected Pryor when Jean returned from stasis, and the youth would be carried to the future, where he would return to present era as Cable. Sinister's machinations would lead to the event known as Inferno, where Cyclops supposedly killed Sinister with an optic blast, although Sinister resurfaced alive and well, when he revealed that there was a third Summers brother.

Sinister was involved in Stryfe's attempted assassination of Xavier,, trading Cyclops & Jean Grey to Stryfe in exchange for their DNA. However, Stryfe actually gave Sinister the Legacy Virus, which would terrorize mutant (and eventually human) life, and lead to the deaths of several mutants.

Sinister later involved himself with Nate Grey and the mutant Threnody. He joined the reestablished Weapon X program as Doctor Robert Windsor, claiming to help mutants escape Weapon X's mutant concentration camp "Neverland," but in reality, he took them to be his test subjects.