As a girl, May Parker was a wild child; she once shouted a proposal to Jimi Hendrix at a concert, and at fifteen she ran away from home, sleeping in a San Francisco basement for awhile. Her family problems were presumably resolved over time, as she now has a good relationship with her mother, who retired to Florida. After marrying Ben Parker, May befriended his brother, Richard, Richard's wife, Mary, and their son, Peter. When Richard and Mary died in a plane crash around the same time May lost her own sister, whom she considered her best friend, May and Ben took Peter in and raised him as their own. May became a responsible adult, working in an office cubicle and attending PTA meetings.

May's life took a tragic turn when Ben was shot dead by a burglar before her eyes. She became the sole guardian to Peter, who started acting up and keeping odd hours She comforted him when he had nightmares, but was unsure if Peter even liked her since he never seemed to be around anymore; in truth, Peter had secretly become the super hero Spider-Man. Terrified she might lose Peter too, May angrily overreacted whenever she couldn't account for his whereabouts, subconsciously pushing him away. One night, May caught Peter coming home extremely late and grounded him, but soon relented; however, reports of Peter's erratic attendance at school continued to cause her concern.

After Peter befriended new classmate Gwen Stacy, May became romantically interested in Gwen's father, John - ironically, the police officer who had investigated Ben's death. When John was killed by a Spider-Man imposter and Gwen's absentee mother refused to take responsibility for her daughter, May took Gwen in. John Stacy's death prompted May to see a therapist to whom she confessed her fear of loss, her guilt over being attracted to John so soon after Ben's death, and her concern that she was only using Gwen as a way of keeping herself too busy to think about the ghosts surrounding her. She also admitted she was terrified of the chaos Spider-Man and his ilk represented, as he seemed to keep appearing during times of crisis in her life. May's therapist helped her see she needed to let herself love people without always fearing she would lose them.

Realizing this seemed to give May new strength. When Peter's employer J. Jonah Jameson unjustly fired Peter, May called Jameson and gave him a piece of her mind; when Mary Jane's father accosted Peter for endangering his daughter, May again defended her nephew. She even held her ground against agents of S.H.I.E.L.D. when they took her into protective custody after several of Spider-Man's enemies escaped. However, tragedy struck again when Gwen was murdered in the Parker's backyard by the creature known as Carnage. With too many bad memories now filling their home, May and Peter made plans to move.