The control of cellular proliferation is key in the proper development of a complex organism, the maintenance of tissue homeostasis and the ability to respond to various hormonal and other inducers. Key in the control of proliferation is the retinoblastoma (Rb) protein which regulates the activity of a family of transcription factors known as E2Fs. The E2F proteins are now recognized to regulate the expression of a large number of genes associated with cell proliferation including genes encoding DNA replication as well as mitotic activities. What has also become clear over the past several years is the intimate relationship between the control of cell proliferation and the control of cell fate, particularly the activation of apoptotic pathways. Central in this connection is the Rb/E2F pathway that not only provides the primary signals for proliferation but at the same time, connects with the p53-dependent apoptotic pathway. This review addresses this inter-connection and the molecular mechanisms that control the decision between proliferation and cell death.