It is now well established that cyclins play a positive role in promoting cell cycle transitions via their ability to associate with and activate their cognate cyclin-dependent kinases (Cdks). Cdk2 associates with cyclins A, D and E, and has been implicated in the control of the G1 to S phase transition in mammals. A novel Cdk-interacting protein, designated p21, Cip1 or WAF1, has been identified in cyclin A, cyclin D1, cyclin E and Cdk2 immunoprecipitates. p21 is a potent, tight-binding inhibitor of Cdks and can inhibit the phosphorylation of Rb by cyclin A-Cdk 2, cyclin E-Cdk2, cyclin D1-Cdk4 and cyclin D2-Cdk4 complexes. Expression of p21 is inducible by wildtype, but not mutant, p53. The mouse homolog of p21 is designated CAP20.