Tumor-suppressor genes (antioncogenes or recessive oncogenes) are cancer genes that achieve their oncogenic effect by mutational inactivation of both normal alleles. By contrast, oncogenes are created from protooncogenes by mutations that lead to aberrant functional activation. Mutation of multiple suppressor genes and/or oncogenes probably is required for the genesis of most human neoplasms. Two well-characterized tumor-suppressor genes, the retinoblastoma gene (rb) on chromosome 13q and p53 on chromosome 17p, frequently are mutated in a broad range of human cancer types. Mutations of these genes have been documented in prostate carcinoma but appear to affect only a subset of cases. Nevertheless, as in other cancers, introduction of normal copies of rb or p53 suppresses the neoplastic properties of prostatic tumor cells carrying mutated alleles of the relevant gene. These results suggest that mutation of rb or p53 is involved in the genesis or progression of some prostate cancers. Frequent allelic losses of certain chromosome arms (especially 8p, 10p and q, and 16q) from prostatic cancer cells may indicate the involvement of novel suppressor genes located in these regions. Although the inactivation of suppressor genes appears to be a common genetic mechanism in human oncogenesis, the rates of mutation of particular genes vary widely with the type of cancer. It is unknown whether prostate cancers with or without mutation of rb, p53, or other suppressor loci differ biologically or prognostically; this is an area of active investigation. Fundamental understanding of the genetic lesions that occur during human oncogenesis has great potential for clinical application in diagnosis, prognosis, and therapy.