The retinoblastoma gene (Rb) was the first tumor suppressor gene to be cloned [Dryja et al., 1986; Friend et al., 1986; Lee et al., 1987], and, as a consequence, has been studied intensively within the context of cell cycle regulation and oncogenesis. However, a number of recent findings indicate that the retinoblastoma gene product (pRb) likely plays an essential role not only in controlling entry into the cell cycle, but also in the terminal differentiation of a number of different cell types [Lee et al., 1994; Gu et al., 1993]. In particular, the phenotype of the Rb nullizygous mice, created by a number of groups using homologous recombination [Jacks et al., 1992: Clarke et al., 1992; Lee et al., 1992], indicates that pRb is essential for normal development of the nervous and hematopoietic systems and may even function to regulate apoptosis [Haas-Kogan et al., 1995]. Although this paper briefly reviews the traditional role of pRB in regulation of cellular proliferation, we focus on the role of pRB in neuronal development and apoptosis. Recent reviews have been published on the role of pRb in cell cycle and transcriptional regulation [Hamel et al., 1992; Cobrinik et al., 1992; Kouzarides, 1993; Hollingsworth et al., 1993; Helin and Harlow, 1993; Sherr, 1994], as well as the relationship between pRb and p53 [Picksley and Lane, 1994; White, 1994].© 1996 Wiley-Liss, Inc.