The Brotherhood of Mutants is a group dedicated to the cause of mutant superiority over humans. Throughout its various incarnations, the Brotherhood's agenda has gravitated towards either subjugating the human race to the will of mutants or eradicating humanity altogether. Magneto formed the Brotherhood of Evil Mutants, including Astra, Toad, Quicksilver, Scarlet Witch, and Mastermind, shortly after the public debut of the X-Men. After a falling out with Astra that led to her quitting the team, Magneto had the Brotherhood initiate an attack upon humans that was thwarted by the X-Men. Magneto then attempted to recruit the thunder god Thor into his Brotherhood, but Thor refused. The Blob was the next candidate for recruitment, but ultimately declined to join after seeing the way Magneto mistreated his followers. Mastermind then sought to recruit Unus the Untouchable; however, he was blackmailed by the X-Men into declining the offer in exchange for reversing his then-amplified powers. During an encounter with the enigmatic Stranger, Magneto and the Toad were captured and taken to the Stranger's homeworld, shortly after which Quicksilver and the Scarlet Witch joined a revamped version of the Avengers led by Captain America.

After a tenure with the subversive organization Factor Three (intended to become a third major world power), Blob, Mastermind, and Unus banded together as a new Brotherhood. Following a failed attempt to settle the score with the X-Men, the trio were able to make the Beast believe he had killed the Avenger Iron Man and manipulated him into joining until he realized the truth and single-handedly defeated them. Eventually returning to Earth, Magneto re-formed the Brotherhood with Blob, Mastermind, Unus, and the Savage Land Mutate Lorelei to assist him in the creation of a being with unlimited power that he dubbed Alpha, the Ultimate Mutant. In an encounter with the Defenders, the rapidly evolving Alpha unleashed his powers, reducing the Brotherhood to a state of infancy. Subsequently restored to adulthood by Eric the Red of the alien Shi'ar race, Magneto formed a new Brotherhood comprising Lifter, Burner, Shocker, Slither, and Peeper. When they failed to capture the mutant with two bodies known as Mister One and Mister Two, Magneto abandoned this team, though they remained together as the Mutant Force and later temporarily became the Resistants.

The mutant shapeshifter Mystique formed her own Brotherhood of Evil Mutants, recruiting Blob, Pyro, Avalanche, Destiny, and her own foster daughter, Rogue. Mystique sent the Brotherhood against Carol Danvers, then known as Ms. Marvel (later Binary and Warbird), which ultimately led to Rogue absorbing and retaining Danvers' powers and memories. Mystique intended for the Brotherhood to assassinate then-anti-mutant Senator Kelly, but they met defeat after the X-Men intervened and were incarcerated. Rogue freed the imprisoned members from captivity, but the male members were quickly recaptured after a struggle with the Galadorian Spaceknight named Rom. Mystique then sought to recruit the Dire Wraith/human half-breed Hybrid as a member; however, he proved too powerful for her to control, and the "Sisterhood" eventually aided Rom in temporarily destroying Hybrid. Subsequent efforts to target the X-Man Angel led to an encounter with Alison Blaire, the Dazzler, with whom Rogue quickly developed a fierce rivalry until Dazzler definitively defeated her.