Miguel O'Hara, an engineer of Irish and Mexican descent, was born after his mother Conchata had an affair with her husband's boss Tyler Stone, though grew up believing his stepfather was also his biological father. As an adult, he worked for Alchemax. He was less than pleased at the corporation's vast control over the city. A genius in the field of genetics, he was being pressured by Tyler Stone to test a process to imprint genetic codes into human physiology. He reluctantly tried the process on a test subject named Mr. Sims. It was a failure - Sims was transformed into a hideous creature and quickly died.

This was the last straw for Miguel: he went to Stone and attempted to hand in his notice. Stone gave and Miguel accepted a drink which, unknown to Miguel had been laced with the highly addictive hallucinogenic drug that bonds to the victim's DNA, called Rapture. As Alchemax was sole manufacturer of the drug, Stone expected that Miguel would be forced to remain with the company. In an attempt to rid himself of the hallucinogen, Miguel decided to try the genetic procedure, which had killed Sims, on himself, as he had input his own original genetic code as a baseline. The process was sabotaged by his supervisor, Aaron Delgato, in the attempt to kill him (the incident would be covered up as an accident). Miguel survived the process; his DNA was spliced with the genes of a spider and gained several powers, though he lost his addiction to Rapture.

Immediately afterwards, Aaron discovered Miguel’s deformities, and started firing at him, despite Miguel begging him to stop, since he thought Miguel sought to kill him. After their skirmish caused an explosion, Aaron almost fell off a ledge, but was caught by Miguel. However, he didn’t know about his recently acquired talons, cutting into Aaron’s arm and causing him to fall to his death. Noticing the chaos, a group Public Eye soldiers were sent to apprehend Miguel. Seeing himself as a freak, Miguel flung himself out the hole in the wall, before coming to his senses and catching himself using his talons. He then snuck away from the building, and leapt onto the hang glider with a member of the Church of Thor so he could escape the Public Eye. When the Thorite asked who he was, he joking responded, "I dunno. The Easter Bunny. Santa Claus. Spider-Man. Take your pick." Due to the Thorite’s blind devotion to his beliefs, he mistook him for Spider-Man, and started hailing “his” name. Overexcited and distracted, the Thorite wrecked their hang glider. Picking up the remains of the hang glider, Miguel tried to hand it to the Thorite, apologizing for the damages, and suggested that they sew it back together. However, the Thorite told Miguel that he should use the tatters as a makeshift mask so that he could easily conceal his face from the Public Eye. Miguel heeded this advice, and returned to his apartment, falling asleep. When he awoke, he regarded his previous experiences as a nightmare, only to discover that the events were, in fact, reality, when he saw his talons. He then touched his chest with the talons, and discovered that they retracted automatically whenever they touched his skin. Miguel’s A.I., Lyla, told Miguel that his brother, Gabriel, was calling him. When Miguel answered, Gabriel told him that he was coming to visit him due to Miguel’s fiancé Dana called him, worried about Miguel. Once Gabriel arrived, Miguel noticed (thanks to his increased eyesight) that Venture, an elite bounty hunter working for Alchemax, was tracking him, due to Alchemax wanting Miguel for research. Seeking to protect his brother, Miguel rushed Gabriel out of his apartment, and made a makeshift costume for himself out of an unstable molecule Day of the Dead costume and material from the damaged Thorite hang glider, and glided out of his apartment window to defend himself against Venture.

However, a group of Thorites interfered in the two’s fight, wanting to protect Miguel, who they believed to be the Harbinger of Thor. The Thorites, not posing a threat to Venture, were easily defeated, and threatened to kill them all unless Miguel surrendered, killing a Thorite to show that he wasn’t bluffing. This caused Miguel to attack Venture, and the two engaged in a fight than ended in Venture capturing Miguel. However, Miguel eventually broke out of his restraints, and damaged Venture’s rocket boots. During the proceeding struggle, Miguel discovered that he could fire webbing from his forearms, blinding Venture. Before falling, Miguel caught himself on a nearby sign. While Venture was disoriented, Miguel picked up a hover car that functioned by repelling itself from the metal streets of Nueva York, and repelled the rifle of Venture from him. Miguel then opened a hole in Venture’s cybernetic leg, and shoved his Combat rod into it, short-circuiting all of his systems. Days later, Miguel returned to his apartment, and filled Lyla in on what had happened.

Originally focused with finding a cure for his condition, Miguel's further adventures as Spider-Man 2099 cause him to realize how ignorant of the world he was and how he had turned a blind eye to the oppression and pain the corporations of the world have caused. He is also surprised at the effect his presence has on the people who have been oppressed for so long, particularly his own mother, who ironically also hates the man her eldest son has become yet admires the exploits of Spider-Man 2099. After this, Miguel decides to embrace his identity as Spider-Man. Donning his costume, he publicly proclaims himself to be an enemy to all the megacorps, saying he will use his powers to fight for ordinary people against those in power who abuse their influence and authority.