Although DNA is the carrier of stable genetic information, this giant molecule exhibits slow turnover in cells as a consequence of endogenous damage. DNA lesions result from hydrolysis, and from exposure to active oxygen and reactive metabolites. These major forms of damage to the heterocyclic bases and to the DNA backbone structure are now well characterized. Most DNA repair enzymes have apparently evolved to prevent genomic instability caused by endogenous lesions, the only exception being those that counteract ultraviolet light damage inflicted by the sun. Despite the efficiency of DNA repair pathways, some forms of endogenous DNA damage still cause mutagenic alterations and may result in human disease.