The retinoblastoma (Rb) tumor suppressor gene and its close relatives p107 and p130 are best known for their function in the control of cell cycle progression. In recent years, however, a new role for these proteins has been emerging as they have been linked with regulation of terminal differentiation of many tissues and cell types. In fact, Rb and its family members have been shown to be involved in multiple stages of the differentiation process including irreversible exit from the cell cycle, protection from apoptosis, induction of cell type specific gene expression and maintenance of the post-mitotic state. They also play a critical role in assuring the orderly progression through all these stages of differentiation.