Mutations of the p53 tumor suppressor gene are found in about 50% of all human cancers. The p53 mutation spectra in these cancers are providing clues to the etiology and molecular pathogenesis of cancer. Recent studies indicate that the p53 protein is involved in several vital cellular functions, such as gene transcription, DNA synthesis and repair, cell cycle arrest, senescence and programmed cell death. Mutations in the p53 gene can abrogate these functions and may contribute to genomic instability and progression to cancer. Characteristic p53 mutation spectra have been associated with dietary aflatoxin B(1) (AFB(1)) exposure and hepatocellular carcinoma (HCC); sunlight exposure and skin cancer; and cigarette smoking and lung cancer. The mutation spectrum also reveals those p53 mutants that provide cells with a selective clonal expansion advantage during the multistep process of carcinogenesis. Although a number of different exogenous carcinogens have been shown to selectively target p53, pieces of evidence supporting the endogenous insult of p53 are accumulating. Furthermore, analysis of a characteristic p53 mutation load in nontumorous human tissue can indicate previous carcinogen exposure and may identify individuals at an increased cancer risk.