Retinoblastoma is a potentially hereditary cancer. Refinement of the genetic and epidemiological analysis of the disease has uncovered two distinct classes of retinoblastoma. Sporadic retinoblastoma is generally unilateral and unifocal, and is diagnosed at the late age of about two years. A few of these sporadic cases are probably due to a germ cell mutation inherited from a parent and hence can be classified as hereditary. Familial retinoblastoma is generally diagnosed at an earlier age, at 11 months, and is typically bilateral and/or multifocal. These observations have been incorporated into a 'two hit' mutational inactivation hypothesis of the origin of retinoblastoma. The molecular cloning and characterization of a candidate retinoblastoma susceptibility gene and its gene product has allowed a critical testing of this hypothesis. All of the predications of the model have been confirmed by experiment. These include inheritance of one mutated retinoblastoma susceptibility (RB) allele as the origin of hereditary retinoblastoma, subsequent loss of the remaining allele upon the genesis of the tumour, the involvement of the same RB gene in both sporadic and hereditary retinoblastoma, the somatic mutation of both RB alleles in sporadic retinoblastoma, the lack of evidence for expression of a normal RB gene product in any retinoblastoma yet examined, the inactivational nature of RB mutations and the recessiveness of these mutated alleles. The RB gene also exhibits suppression of neoplastic properties when introduced into retinoblastoma cells and also into some other tumour cells. These results mutually reinforce the two hit inactivation hypothesis as well as the cloned gene's correct identification as the retinoblastoma susceptibility locus. The confirmation of this hypothesis is, therefore, nearing completion. The definitive proof is achievable with the advent of chimeric mouse technology, which will allow construction of mice with one or both RB alleles that have been inactivated by mutation. Analysis of such mice may allow us to determine if inactivation of both RB alleles is necessary and sufficient for the development of retinoblastoma and possibly other tumour types. The molecular isolation of the RB gene is an important achievement in research on cancer. For the first time, it has become possible to examine, at the molecular level, genes which suppress the tumorigenicity of cancer cells. Analysis of such cloned genes should yield insight into mechanisms of oncogenesis, gene regulation and cellular differentiation complementary to the knowledge which has long been accumulating from the study of oncogenes.