The p53 tumor-suppressor pathway is dismantled in the development of most cancers. Mice with various p53 mutant alleles either singly or in combination with other genetic alterations are predisposed to tumor development. Here, we review studies utilizing p53 mutant mice that have recapitulated and informed clinical observations. These studies have demonstrated the p53 contribution, sometimes beneficial and sometimes detrimental, to treatment response in lymphomas, and lung and breast cancers. Further, we examine how p53 mutant mouse models have been used to test the efficacy of p53 reactivation as a therapeutic strategy.