D-type cyclins couple extracellular signals to the biochemical machinery that governs progression through G1 phase of the mammalian cell division cycle. Induced by growth factor stimulation, D-type cyclins assemble with cyclin-dependent kinases CDK4 and CDK6 to form holoenzymes that facilitate exit from G1 by phosphorylating key substrates, including the retinoblastoma protein. Activation of the holoenzymes is antagonized by polypeptide inhibitors of CDK activity, which are induced by antiproliferative signals. Once cells pass a late G1 restriction point, cyclin-D-dependent kinases are unnecessary for completion of the cell cycle, implying that their primary role is to sense the cell's readiness to replicate DNA and to enforce the commitment to enter S phase.