The availability of p53 knockout mice generated by gene targeting has enabled us to investigate the functional role of the p53 tumor suppressor gene in initiation, promotion, and progression of carcinogenesis in vivo, using mouse skin as a model system. The number, size, and growth rate of benign papillomas were not increased in the p53 heterozygous mice in comparison with wild type. The p53 null mice showed a reduced yield of papillomas, but these underwent much more rapid malignant progression, with some poorly differentiated carcinomas developing after only 10 weeks of promotion. Progression rate was also greater in heterozygous than in wild-type mice and was associated with loss of the remaining wild-type allele. Most tumors from all groups had activating mutations in the H-ras gene. Absence of p53, therefore, does not augment the frequency of initiation or the rate of promotion but greatly enhances malignant progression.