Deregulated cell proliferation is the hallmark of cancer, and convergent data from the fields of cell-cycle research and molecular oncology have revealed the key role played by abnormalities of the cell-cycle control genes in multistep tumorigenesis. Along with the p53-mediated DNA damage checkpoint, the G1-governing pathway of D-type cyclins, their partner cyclin-dependent kinases (Cdk), Cdk inhibitors, and the retinoblastoma protein constitute a functional unit and prominent oncogenic target. We have learned a great deal about the molecular basis of G1 phase progression and G1/S transition, their proto-oncogenic defects, and potential clinical significance including diagnostic and prognostic applications and new approaches to gene therapy of cancer.