Proliferation and differentiation are tightly coupled processes, so that a final cell cycle is often linked to the initiation of cell differentiation. The flux in cell cycle proteins during this process is commonly assumed to simply control the final cell cycle exit. However it now appears that cell cycle proteins can also play a role in the decision to continue cycling or to terminally differentiate. A subset of the G1 to S phase transition proteins, D-type cyclins, Rb family proteins and the CDK inhibitors, are particularly involved in the commitment to differentiation. Cell cycle proteins can sequester or modify activators of differentiation pathways, while simultaneously performing their cell cycle functions as illustrated by their roles in terminal differentiation in mammary epithelium. G1 to S phase cell cycle proteins, particularly cyclin D1, are commonly altered in breast cancer and contribute to breast tumorigenesis, presumably by increasing proliferation. However the capacity for cell cycle proteins to also influence differentiation may influence tumour progression, and may alter the efficacy of differentiation-based therapeutics.