The cyclin-dependent kinase CdkP associates with cyclins A, D, and E and has been implicated in the control of the Gl to S phase transition in mammals. To identify potential Cdk2 regulators, we have employed an improved two-hybrid system to isolate human genes encoding Cdk-interacting proteins (Cips). C/P7 encodes a novel 21 kd protein that is found in cyclin A, cyclin Dl, cyclin E, and Cdk2 immunoprecipitates. p21cfp’is a potent, tight-binding inhibitor of Cdks and can inhibit the phosphorylation of Rb by cyclin A-Cdk2, cyclin E-CdkP, cyclin Dl-Cdk4, and cyclin D2-Cdk4 complexes. Cotransfection experiments indicate that C/PI and SV40 T antigen function in a mutually antagonistic manner to control cell cycle progression.