On the basis of current knowledge, control of the G1/S phase transition is largely a matter of regulating a set of specific cyclin dependent kinase (CDK) activities. In mammalian cells, the G1/S specific CDK activities are composed of complexes between D type cyclins and either CDK4 or CDK6 and between cyclin E (and possibly cyclin A) and CDK2. A variety of internal and external signals regulate G1/S specific CDKs by modulating cyclin availability, the levels of CDK inhibitory proteins and the phosphorylation status of CDKs. Although much is now known about the regulation of G1/S specific CDKs, the only well characterized substrate to date is the retinoblastoma gene product, RB. Phosphorylation of RB by CDKs neutralizes its cell cycle inhibitory properties, allowing progression of G1 to S phase. Not surprisingly, many components of the cell cycle regulatory machinery, including CDKs, CDK inhibitors and CDK substrates, are important targets of mutations that lead to human malignancy.