Efficient and accurate cell cycle exit is intimately linked to cellular differentiation, and by inference, to the prevention of tumorigenesis. Perhaps the most important axis of control for this process involves the interactions of the E2F family of DNA binding proteins with the retinoblastoma (Rb) and Rb-related “pocket protein” (p107 and p130) family of tumor suppressors. Not surprisingly, alterations in this pathway are present in a large number of human malignancies. The molecular basis for the controls exercised by the Rb family of proteins has been widely investigated, but is still not completely understood. Elegant in vitro studies had previously suggested the participation of histone deacetylase (HDAC)-associated Sin3B in E2F-mediated repression. Using genetically modified mice, we have recently uncovered a role for the Sin3B protein as a specific and essential actor in promoting cell cycle exit via the E2F-Rb pathway. We demonstrated its absolute requirement not only for cell cycle exit in vitro and in vivo, but also for biological processes linked to cellular differentiation. These observations strongly suggest that Sin3B plays an essential role in coordinating the chromatin modifying activities required for the transient repression of pro-proliferation genes in quiescence, as well as stable silencing of these genes upon terminal differentiation.