Carcinogenesis is a multistage process driven by carcinogen-induced genetic and epigenetic damage in susceptible cells that gain a selective growth advantage and undergo clonal expansion as the result of activation of protooncogenes and/or inactivation of tumor suppressor genes. Therefore, the mutational spectra of chemical and physical carcinogens in these critical genes are of interest to define endogenous and exogenous mutational mechanisms. The p53 tumor suppressor gene is ideally suited for analysis of the mutational spectrum. Such an analysis has revealed evidence for both exogenous and endogenous molecular mechanisms of carcinogenesis. For example, an informative p53 mutational spectrum of frequent G----T transversions in codon 249 is found in hepatocellular carcinomas from either Qidong, People's Republic of China, or southern Africa. This observation links exposure to aflatoxin B1, a known cancer risk factor in these geographic regions, with a specific mutation in a cancer-related gene. Other studies indicate that abnormalities in genes controlling the cell cycle may cause genomic instability and increase the probability of neoplastic transformation. Finally, mechanistic understanding of carcinogenesis is leading to improved cancer risk assessment and to the identification of individuals at high cancer risk.