The Cdk-Rb-E2F pathway integrates external and internal signals to control progression at the G1/S transition of the mammalian cell cycle. Alterations in this pathway are found in most human cancers, and specific cyclin-dependent kinase Cdk4/6 inhibitors are approved or in clinical trials for the treatment of diverse cancers. In the long-standing paradigm for G1/S control, Cdks inactivate the retinoblastoma tumor suppressor protein (Rb) through phosphorylation, which releases E2F transcription factors to drive cell-cycle progression from G1 to S. However, recent observations in the laboratory and clinic challenge central tenets of the current paradigm and demonstrate that our understanding of the Rb pathway and G1/S control is still incomplete. Here, we integrate these new findings with the previous paradigm to synthesize a current molecular and cellular view of the mammalian G1/S transition. A more complete and accurate understanding of G1/S control will lead to improved therapeutic strategies targeting the cell cycle in cancer.