A minor fraction of cancer occurs in persons who have strong dominantly transmissible genetic predisposition. Retinoblastoma and Wilms' tumor are the most thoroughly studied examples. Hereditary cases involve mutations at the same chromosomal sites. In most carriers of mutation the change cannot be visualized; in some, it is a visible deletion. A significant fraction of nonhereditary cases involve deletion at the same site in tumor cells only, suggesting that mutation at this site is necessary for the initiation of tumor, whether hereditary or not. This may be a general model for human cancer. The initiating mutation is not sufficient, however, since only rare cells are transformed. A second event may be genetic, such that recessive loss of the gene occurs. A two-event genetic model for a major fraction of human cancers is also compatible with the well-established, age-specific incidence of various cancers.