Apoptosis and long term enterocyte survival were examined in vivo after exposure to three cytotoxic agents (Cisplatin, Nitrogen Mustard and N-methyl-N-nitrosourea (NMNU/MNU)) within mice either singly or doubly mutant for p53 and Msh2. P53 deficiency caused abrogation of the immediate apoptotic response to each agent, but only led to increased survival after cisplatin treatment. Msh2 deficiency reduced the apoptotic response to each agent, but only led to increased crypt survival after NMNU treatment. Following cisplatin treatment, the response of (Msh2(-/-), p53(-/-)) mice paralleled that of the p53(-/-) mice. A delayed wave of apoptosis was observed in both p53(-/-) and (Msh2(-/-), p53(-/-)) mice demonstrating this phenomenon to be independent of functional Mismatch repair (MMR). We conclude that loss of either p53 or Msh2 dependent apoptosis does not predict long-term crypt survival in vivo, however genetic status clearly can modulate survival for some agents such as cisplatin.