Genetic evidence from retinoblastoma patients and experiments describing the mechanism of cellular transformation by the DNA tumor viruses have defined a central role for the retinoblastoma protein (pRB) family of tumor suppressors in the normal regulation of the eukaryotic cell cycle. These proteins, pRB, p107, and p130, act in a cell cycle-dependent manner to regulate the activity of a number of important cellular transcription factors, such as the E2F-family, which in turn regulate expression of genes whose products are important for cell cycle progression. In addition, inhibition of E2F activity by the pRB family proteins is required for cell cycle exit after terminal differentiation or nutrient depletion. The loss of functional pRB, due to mutation of both RB1 alleles, results in deregulated E2F activity and a predisposition to specific malignancies. Similarly, inactivation of the pRB family by the transforming proteins of the DNA tumor viruses overcomes cellular quiescence and prevents terminal differentiation by blocking the interaction of pRB, p107, and p130 with the E2F proteins, leading to cell cycle progression and, ultimately, cellular transformation. Together these two lines of evidence implicate the pRB family of negative cell cycle regulators and the E2F family of transcription factors as central components in the cell cycle machinery.