The retinoblastoma gene, Rb, was originally identified as the tumor suppressor gene mutated in a rare childhood cancer called retinoblastoma (reviewed in ). Subsequent studies showed that Rb functions in a pathway that is often functionally inactivated in a large majority of human cancers. Interestingly, recent studies showed that in certain types of cancers, Rb function is actually required for cancer development. The intimate link between the Rb pathway and cancer development suggests that the status of Rb activity can potentially be used to develop targeted therapy. However, a prerequisite will be to understand the role of Rb and its interaction with other signaling pathways in cancer development. In this review, we will discuss the roles of Rb in proliferation, apoptosis and differentiation by reviewing the recent findings in both mammalian systems and different model organisms. In addition, we will discuss strategies that can be employed that specifically target cancer cells based on the status of the Rb pathway.