Dr. Curtis Connors was an Army surgeon whose right arm was amputated when it became gangrenous from a war wound. Unable to remain a surgeon, Connors undertook the scientific study of reptiles, soon becoming a leading authority. Reptiles still possess the ability to regenerate missing limbs whereas mammals have evolved away from that trait. Connors discovered the precise chemical substance that confers this ability, and administered it to himself. He succeeded in regenerating his missing arm but the mutagenic effects of the chemical did not end and caused a body wide transformation to a reptilian-humanoid form.

Possessed by a primitive but cunning reptilian mind, the Lizard intended to gather a reptile army that would supplant humanity as Earth's ruling species. But Spider-Man stopped the Lizard's schemes, using Connors' chemicals and scientific knowledge to create a serum that reversed the original formula's effects. However, the mutations the serum enacted remain part of Connors' genetic makeup. Though he has gone long periods without transforming into his reptilian alter ego, the scientist has never been able to fully free himself from the curse of the Lizard.