The retinoblastoma gene was identified over a decade ago as the first tumor suppressor. Although the gene was initially cloned as a result of its frequent mutation in the rare pediatric eye tumor, retinoblastoma (Friend et al. 1986; Fung et al. 1987; Lee et al. 1987), it is now thought to play a fundamental role in cellular regulation and is the target of tumorigenic mutations in many cell types. The retinoblastoma gene encodes a 928–amino acid phosphoprotein, Rb, which arrests cells in the G1 phase (Weinberg 1995). Rb is phosphorylated and dephosphorylated during the cell cycle; the hyperphosphorylated (inactive) form predominates in proliferating cells, whereas the hypophosphorylated (active) form is generally more abundant in quiescent or differentiating cells (Chen et al. 1989). As a demonstration its tumor suppressor activity, Rb was reintroduced into Rb-deficient tumor cells and it blocked several features of the malignant phenotype (Huang et al. 1988). Mutations affecting the retinoblastoma gene are frequently encountered, not only in retinoblastoma but also in other cancers such as osteosarcoma, small cell lung cancer, prostate cancer, and breast cancer (Friend et al. 1986; Fung et al. 1987; Harbour et al. 1988; Lee et al. 1988; T’Ang et al. 1988; Bookstein et al. 1990). Indeed, children with hereditary retinoblastoma have 30-fold increased risk of developing a second, nonocular malignancy, especially bone and soft tissue sarcomas in adolescence and cutaneous melanomas in adulthood (Eng et al. 1993; Moll et al. 1997). These second neoplasms occur almost exclusively in patients who have germ-line mutations in the retinoblastoma gene. As a further indication of its fundamental role in tumor suppression, Rb can be functionally inactivated by constitutive hyperphosphorylation in tumors that do not have mutations in the retinoblastoma gene (Sherr 1996). In addition, DNA tumor viruses express oncoproteins, such as adenovirus E1A, SV40 large tumor antigen, and human papillomavirus (HPV) E7, that bind and inactivate