The Friends of Humanity was founded by Graydon Creed and rogue S.H.I.E.L.D. agents pertaining anti-mutant sentiments. The F.O.H. had been initially discretely focusing on researching and developing anti-mutant countermeasures.
Graydon Creed had hired a rogue Weapon X scientist to use other mutants, such as Wolverine and Sabretooth, as "mutant-slayers"; however, the project was foiled and inadvertently destroyed by Nightcrawler and Shadowcat. The Weapon X scientist was personally killed by Creed for his failures.
The F.O.H. would personally faced the X-Men and their powerful ally Superman, who foiled their operations every time. The organization was persistent in trying not only to eliminate mutants but Superman himself that Graydon Creed loathed the Man of Steel for the human public to view him as a hero.
Funding of resources were secretly provided to the F.O.H. by Bolivar Trask, a S.H.I.E.L.D. military scientist, and from unknown benefactors that included Kryptonite-based weaponry into their arsenal. Unbeknownst to the F.O.H., their mysterious benefactors were Doctor Doom and the mutants Magneto and Sebastian Shaw, who manipulated the F.O.H. in their agenda into showing Superman the true nature of humanity's bigotry and prejudice that he had been saving and convincing the Man of Steel to lead mutantkind over humanity.
Due to the manipulations of Doom, Magneto, and Shaw, the F.O.H. resurrected Bolivar Trask's Sentinel Project and constructing a weapons-line of mutant-hunting Sentinels. This culminated in the exposure of Superman and the X-Men's, and generally mutants, to the public, and the capture of Professor Charles Xavier to their S.H.I.E.L.D. base in New Mexico and the destruction of the Xavier Institute. Graydon Creed plotted for the genocide of mutantkind gathering on Genosha by launching the Sentinels, but only to be foiled by the X-Men, the Avengers, Fantastic Four, and the newly-created Justice League. In the aftermath, the F.O.H. were acknowledge of Superman's alien origins that led Graydon Creed into labeling aliens and other non-humans as more definite threats to humanity.
The F.O.H. later attempted to destroy Genosha, but the plan was thwarted by the Justice League. In a last desperate attempt to destroy the Justice League and their allies, the F.O.H. managed to seize control of the Xavier Institute and took several humans who were related to mutants hostage, demanding that Superman's technology be surrendered to them, that their imprisoned comrades be freed, and that aliens, mutants and non-humans would thereafter leave the planet. At the same time, they sent assassins to kill politicians who supported mutant-human coexistence, such as Edward Kelly. They also had Jason Stryker, the abused mutant son of F.O.H. member William Stryker, probe Xavier's mind in an attempt to learn the identity of Superman's foster family.
From this point on, their plans quickly began to derail. The assassination attempts were thwarted by the Justice League, and the media used this as an opportunity to interview numerous humans, who unanimously condemned their so-called "friends" as Nazis and monsters. Meanwhile, the Justice League and the X-Men assaulted the academy on all sides, easily taking out the group's outer defenses. Graydon desperately tried to reain control by threatening the hostages, but Superman managed to demoralize Graydon's men by revealing the news reports that revealed humanity's contempt for the F.O.H. and by revealing Graydon's real reason for his actions: his abusive childhood. With his control lost, Graydon could only watch in shock as the heroes rescued the hostages (including Professor Xavier), defeated his remaining supporters, and wiped out the Sentinels. Graydon and Stryker tried to escape, but were attacked and overpowered by Nightcrawler and Mystique.
Realizing that he had lost, but thinking he could inspire others to continue his work, Graydon tried to initiate a last Sentinel attack on Genosha, but the Justice League destroyed the Sentinels before they could arrive at their destination. Following this monumentous defeat, Graydon and his men were finally taken into custody, with the exception of Michael Matthews and his son, Duncan, who narrowly escaped. Jason, meanwhile, was taken in by Professor Xavier.