The Legacy Virus was a devastating plague that ripped through the mutant population, killing hundreds and mutating so that it affected baseline humans as well, until it was cured almost overnight by the sacrifice of the superhero Colossus, a member of the X-Men.
Origin & major infection
The villain Stryfe gave Mister Sinister a canister that he claimed contained 2,000 years worth of genetic material from the Summers bloodline. When Gordon Lefferts, a scientist working for Sinister, opened the canister after Stryfe was apparently killed by Cable, they found nothing inside. Far worse than that, the canister actually contained a plague, Stryfe's "legacy" to the world.
When Colossus' sister Illyana fell ill and died, he left the X-Men and joined Magneto's Acolytes, but later returned. His teammate Beast developed a cure for the virus, but in order for it to be quickly dispersed, a mutant had to sacrifice himself. Colossus did not want any more people to suffer his sister's fate, so he injected himself with the Legacy cure and activated his mutant powers, transforming his body into organic steel. This supercharged the Legacy cure and simultaneously killed him and stopped the spread of the Legacy virus.
Kavita Rao's attempts & Colossus revival
Failing to success, Kavita Rao, a colleague to McCoy, was visited a few weeks after Colossus' sacrifice by Ord, who revealed to have resurrected him using alien technology. He was then used as a test subject for an experimental formula that would reverse mutations, was eventually rescued by the X-Men.
Unfortunately, this rapid cure had unforeseen geopolitical effects. Thousands of Legacy-infected mutants and mutates had been quarantined on the island nation of Genosha, which was controlled by Magneto at the time. The instant cure gave Magneto a vast army overnight and allowed him to begin carrying out his plans for world conquest.
It was revealed that Singularity Investigations was creating a virus designed to kill mutants. While Jamie Madrox referred to this as the Legacy Virus, it is unclear whether Singularity is actually recreating Stryfe's virus or merely engineering a new one with a similar purpose.
During the "Secret Invasion" storyline, Beast discovered that the Legacy Virus can infect Super-Skrulls that have X-Men-based powers. Cyclops decided to have the Legacy Virus placed on the outfits of the surrendering X-Men in order to infect the Skrulls. This worked and thwarted the Skrull's invasion of San Francisco.
Later, the Sapien League and the Leper Queen, under Bastion's control, infected Beautiful Dreamer; Fever Pitch; Boom-Boom; Hellion and Surge, a new strain of the Legacy Virus and set them to blow up, in order to accuse the mutant population of terrorism, and create the Mutant Response Division (MRD). Only the two first finally blew up, killing thousands of humans before X-Force aborted the Sapien League's plan.
The Legacy Virus was actually a viroid and was released by Stryfe, a terrorist from approximately 2,000 years in the future. It originally existed in two forms, Legacy-1 and Legacy-2, but later mutated into a third form, Legacy-3; all were airborne agents.
Legacy-1 and Legacy-2 searched for a target organism's "X-factor", the sequence of mutant genes that gave a mutant their superpowers. If it did not find an activated X-factor in the target, the viroid would die off, leaving the person completely unaffected. If, however, it did detect the X-factor, it would begin inserting introns (junk DNA sequences) into the transcription codings of the victim's mutant RNA, the process commonly being triggered after the patient used their powers for the first time after contracting the disease. The result was a major compromise of the replication and transcription process so disruptive as to eventually render the body incapable of creating healthy cells, ultimately resulting in the death of the victim.
Legacy-1 attacked general transcription and replication of all cells, a messy and non-selective process that resulted in a condition akin to a fast-replicating cancer. This is the version that infected Illyana Rasputin, sister of Colossus. Legacy-2, however, was much closer to Stryfe's original template and more in tune to his desire to stir a species war between humans and mutants. Its attacks were selective, working only on the X-factor genes. The net result was that a victim would eventually lose control of his superhuman powers. In addition to developing at a far slower rate than Legacy-1, victims of Legacy-2 developed skin lesions, fever, cough and overall weakness (symptoms displayed by the telepathic X-Man Revanche). The slow nature of Legacy-2 is why St. John "Pyro" Allerdyce survived for years following his initial infection.
Legacy-3 was a complete fluke, accidentally created in the body of the mutant woman known as Infectia. Her powers allowed her to scan and visualize the genetic structure of a living being and then alter it according to her own whims; she was essentially a walking genetics laboratory. Infectia had herself been infected with the Legacy Virus, which her own powers tried to stave off. In doing so, they caused a replication error in the Legacy-2 viroid that was killing her. The viroid's conditioning-to not infect if no X-gene was found in the host-was stripped. When Henry McCoy opened Infectia's containment chamber in an act of compassion to allow her one final look at the night sky, he inadvertently released this new "free agent" strain. Legacy-3 was capable of infecting any living being that fit within the parameters of its general original template; that is, hominids only, not canines, felines, etc. Moira MacTaggert, long-time ally of the mutant X-Men and one of Earth's top geneticists, seemed to have been the first non-mutant human to be infected with Legacy-3. She passed on the data she had gathered to McCoy, before being killed by an explosion, at her research station on Muir Island, caused by the shapeshifting terrorist Mystique. Professor X did manage to telepathically retrieve the critical information before Moira died, and Beast was able to synthesize the cure a few weeks later. Though one that had a price; the virus had first been released by the death of the first victim, so the release of the cure would cause the same reaction. They vowed to keep working until a safer cure could be found. Colossus, whose little sister Illyana had succumbed to the Virus months before, could not abide by that decision and injected himself with the cure, sacrificing his life to save the world from the disease. 
The Legacy Virus was based on a virus created by Apocalypse in the distant future, which was intended to kill the remaining non-mutants. At the time that this alternate version of Apocalypse was killed, the virus had not been perfected, and much like Legacy-3, it targeted all humans indiscriminately. As a result, this virus was never deployed, until Stryfe acquired it and altered it for his own purposes.
Mystique had also created (or commissioned the creation of) a strain of the Legacy viroid that only attacked non-mutant humans, leaving mutants completely untouched.
- Absalom: Virtual immortality, ability to extend razor-sharp spines from his body. Killed by Selene.
- Abyss: Malleable body houses a dimensional vortex. Was saved from death when Colossus sacrificed himself to release the cure.
- Bradley, Chris : Bio-Electrostatic generation/manipulation. Survived the Legacy Virus.
- Burke: Killed by the Virus.
- Feral: Feline appearance. Survived the Legacy Virus.
- Infectia: Mutagenic touch. Killed by the Legacy Virus.
- Lefferts, Gordon: Revealed to have been the first victim killed by the Legacy Virus.
- MacTaggart, Moira: Publicly designated as the first human to contract the Legacy Virus.
- Multiple Man: Duplicate infected  and killed.
- Illyana Rasputina: Magic user, chrono-variant teleportation. Killed by the Legacy Virus. Later revived.
- Mastermind: Illusionist. Killed by the Legacy Virus.
- Maverick: Healing factor put the Legacy Virus into remission.
- Mutate #24601: Only Mutate "named"; many others infected and presumed killed.
- Nicodemus: Undefined fire-based abilities. Revealed to have been killed by the Legacy Virus.
- Psynapse: Killed by teammates for being infected and causing him to be "unfit".
- Pyro: Psionic manipulation (but not generation) of fire. Killed by the Legacy Virus after saving Senator Kelly from an assassination attempt.
- Revanche: Telepathy, psionic blade generation. Mercy-killed by Matsu'o Tsurayba before succumbed to the Virus
- Numerous X-Skrulls
- The Legacy Virus is a Class X Pathogen.
- The Legacy Virus storyline ran through various Marvel comics titles from 1993 to 2001.
- Some fans have compared the Legacy Virus, to early rumors of HIV, and AIDS. Both effect the production of healthy cells, and were primarily felt by a minority group (LV mutants, HIV Homosexuals) and had early interest in research for a cure and government backing to aid in such an endeavor be slim, often associated with prejudice towards the inflicted minority group and the belief that as long as it primarily affected that group nothing would be done to stop it. Some even believed HIV was a government conspiracy.
- Exiles #20 portrayed an alternate reality (Earth-8545) where the Legacy Virus had merged with Warlock, after his attempt to save Cypher from infection backfired.