Carcinogenesis is a multistage process involving the inappropriate activation of normal cellular genes to become oncogenes, e.g., ras, and the inactivation of other cellular genes called tumor suppressor genes. p53 is the prototypic tumor suppressor gene that is well suited as a molecular link between the causes of cancer, i.e., carcinogenic chemical and physical agents and certain viruses, and the development of clinical cancer. The p53 tumor suppressor gene is mutated in the majority of human cancers. Genetic analysis of human cancer is providing clues to the etiology of these diverse tumors and to the functions of the p53 gene. Some of the mutations in the p53 gene reflect endogenous causes of cancer, whereas others are characteristic of carcinogens found in our environment. In geographic areas where hepatitis B virus and a dietary chemical carcinogen, aflatoxin B1, are risk factors of liver cancer, a molecular signature of the chemical carcinogen is found in the mutated p53 gene. A different molecular signature in the p53 gene is found in skin cancer caused by sunlight. Because mutations in the p53 gene can occur in precancerous lesions in the lung, breast, esophagus, and colon, molecular analysis of the p53 gene in exfoliated cells found in either body fluids or tissue biopsies may identify individuals at increased cancer risk. p53 mutations in tumors generally indicate a poorer prognosis. In summary, the recent history of p53 investigations is a paradigm in cancer research, illustrating both the convergence of previously parallel lines of basic, clinical, and epidemiologic investigation and the rapid translation of research findings from the laboratory to the clinic.