D-type cyclins integrate mitogen-dependent signals to enforce progression through the frst gap phase (G1) of the cell division cycle. In simplest terms, three mammalian D-type cyclins (D1, D2, and D3), induced in a cell lineage-specifc fashion in response to extracellular signals, interact with two cyclin-dependent kinases (CDK4 and CDK6) to form holoenzyme complexes that phosphorylate the retinoblastoma protein (RB). In turn, RB phosphorylation, reinforced by other CDKs expressed later in G1 phase, inactivates the suppressive effects of RB on transcription factors that induce genes required for DNA replication. All steps in the life history of individual D-type cyclins, including their transcriptional induction, translation, assembly with CDK4 and CDK6, and their rapid turnover via ubiquitinmediated proteolysis, are governed by mitogen signaling. Hence, progression through the G1 phase of the mammalian cell cycle is tied to extracellular signals that ultimately influence cell division. Analysis of phenotypes of mice lacking D cyclins has highlighted their individual and combinatorial lineage-specifc activities during mammalian development. The genes encoding D-type cyclins and their dependent kinases, CDK4 and CDK6, are proto-oncogenes implicated in many forms of cancer. Genetic or biochemical disruption of cyclin D-dependent CDK signaling can restrain cancer development and progression. Here, we highlight the founding discoveries.