We cloned~ 27~‘p’, a cyclin-dependent kinase inhibitor implicated in Gl phase arrest by TGFp and cell-cell contact.~ 27~‘P’associates with cyclin E-Cdk2 complexes in vivo and in vitro, prevents their activation, and inhibits previously activated complexes, and~ 27~‘P’overexpression obstructs cell entry into S phase.~ 27~‘P’potently inhibits Rb phosphorylation by cyclin E-Cdk2, cyclin A-Cdk2, and cyclin D2-Cdk4.~ 27~‘p’is highly conserved and broadly expressed in human tissues, and its mRNA levels are similar in proliferating and quiescent cells.~ 27~‘P’has a region of sequence similarity to~ 21~‘P”‘““~‘, the Cdk inhibitor whose transcription is stimulated by~ 53. A~ 27~‘~’peptide corresponding to this region retains Cdk inhibitory activity. We suggest that cell contact, TGFP, and~ 53 all restrain cell proliferation through related Cdk inhibitors.