Gene mutations in invertebrates have been identified that extend life span and enhance resistance to environmental stresses such as ultraviolet light or reactive oxygen species. In mammals, the mechanisms that regulate stress response are poorly understood and no genes are known to increase individual life span. Here we report that targeted mutation of the mouse p66^shc gene induces stress resistance and prolongs life span. p66^shc is a splice variant of p52^shc/p46^shc (ref. ), a cytoplasmic signal transducer involved in the transmission of mitogenic signals from activated receptors to Ras. We show that: (1) p66^shc is serine phosphorylated upon treatment with hydrogen peroxide (H₂O₂) or irradiation with ultraviolet light; (2) ablation of p66^shc enhances cellular resistance to apoptosis induced by H₂O₂ or ultraviolet light; (3) a serine-phosphorylation defective mutant of p66^shc cannot restore the normal stress response in p66^shc-/- cells; (4) the p53 and p21 stress response is impaired in p66^shc-/- cells; (5) p66^shc-/- mice have increased resistance to paraquat and a 30% increase in life span. We propose that p66^shc is part of a signal transduction pathway that regulates stress apoptotic responses and life span in mammals.