Mutations in atm and p53 cause the human cancer-associated diseases ataxia-telangiectasia¹ and Li-Fraumeni syndrome^2,3, respectively. The two genes are believed to interact in a number of pathways^4–6, including regulation of DNA damage–induced cell-cycle checkpoints⁷, apoptosis and radiation sensitivity⁸, and cellular proliferation⁹. Atm-null mice^10–12, as well as those null for p53^13,14, develop mainly T-cell lymphomas, supporting the view that these genes have similar roles in thymocyte development. To study the interactions of these two genes on an organismal level, we bred mice heterozygous for null alleles of both atm and p53 to produce all genotypic combinations. Mice doubly null for atm and p53 exhibited a dramatic acceleration of tumour formation relative to singly null mice, indicating that both genes collaborate in a significant manner to prevent tumorigenesis. With respect to their roles in apoptosis, loss of atm rendered thymocytes only partly resistant to irradiation-induced apoptosis, whereas additional loss of p53 engendered complete resistance. This implies that the irradiation-induced atm and p53 apoptotic pathways are not completely congruent. Finally—and in contrast to prior predictions^4,6—atm and p53 do not appear to interact in acute radiation toxicity, suggesting a separate atm effector pathway for this DNA damage response and having implications for the prognosis and treatment of human tumours.