Retinoblastoma gene (Rb) is the prototype of tumor suppressors. Germline mutation in the retinoblastoma gene is susceptible to cancer and reintroduction of wild-type Rb is able to suppress neoplastic phenotypes. The fundamental cellular functions of Rb in the control of cell growth and differentiation are important for its tumor suppression. In general, cancer susceptibility caused by inactivation of a tumor suppressor gene results from genome instability. Accordingly, Rb may function in the maintenance of chromosome stability by influencing mitotic progression, faithful chromosome segregation, and structural remodeling of mitotic chromosomes. Rb is also implicated in the regulation of replication machinery and in the control of cell cycle checkpoints in response to DNA damage, further supporting such a role for Rb. Moreover, the mechanistic basis for Rb-mediated transcriptional repression has revealed its connection to global chromatin remodeling. It is likely that Rb suppresses tumor formation by virtue of its multiple biological activities, and a theme throughout its multiple cellular functions is its central role in controlling activities that involve chromatin remodeling. A model in which Rb controls global genome fluidity is thus proposed. Finally, a recent study provides direct evidence indicating that loss of Rb function leads to genome instability. Therefore, tumor suppressors have a common role in the maintenance of genome stability, and such a role may be pivotal for their functions in tumor suppression.