Proper regulation of cellular proliferation is critical for normal development and cancer prevention. Most, if not all, cancer cells contain mutations in the Rb/E2F pathway, which controls cellular proliferation. Inactivation of the retinoblastoma (Rb) family of proteins can occur through Rb loss, mutation, or inactivation by cellular or viral oncoproteins leading to unrestrained proliferation and, often times, results in apoptosis. The loss of growth control occurs primarily by derepression and activation of the E2F transcription factors. E2F1 in particular, serves as the primary link between loss of Rb function and activation of p53-dependent apoptosis. E2F1 function is crucial for responding to loss of proper Rb-mediated growth control to activate p53 and the apoptotic program. Recently, we described the requirement for the DNA damage response proteins Atm, Nbs1, and Chk2 in the E2F1 apoptosis pathway. These findings suggest that there may be a more intimate relationship between the apoptosis pathways resulting from loss of proper Rb-mediated growth control and apoptosis resulting from the accumulation of DNA damage.