Cancer is thought to arise from the accumulation of several genetic mutations in a single cell. Until recently, the only tumorigenic mutations that have been studied in detail are those that activate oncogenes. The discovery of tumor suppressor genes, for which inactivating mutations elicit tumorigenesis, has added a new dimension to our understanding of neoplasia. The retinoblastoma susceptibility gene RB is the prototype tumor suppressor gene and has been shown to suppress the transformed phenotype for several different cancers. Additional studies have revealed other tumor suppressor genes that may operate in a variety of tissues through a variety of mechanisms. These mechanisms may regulate the choice between cellular proliferation and differentiation and appear to involve such processes as the initiation of DNA replication, regulation of expression of certain genes, intercellular communication and adhesion, and the transduction of external signals to intracellular effectors. The elucidation of these mechanisms will enhance our understanding of both oncogenesis and the fundamental operations of the cell. [J Natl Cancer Inst 83:91–96, 1991)