The prototypic oncogene c-MYC encodes a transcription factor, which can drive proliferation by promoting cell cycle re-entry. However, the mechanisms through which c-MYC achieves these effects have been unclear. Using serial analysis of gene expression (SAGE), we have identified the cyclin dependent kinase 4 (CDK4) gene as a transcriptional target of c-MYC. c-MYC induced a rapid increase in CDK4 mRNA levels through four highly conserved c-Myc binding sites (MBS) within the CDK4 promoter. Cell cycle progression is delayed in c-MYC-deficient RAT1 cells, and this delay was associated with a defect in CDK4 induction. Ectopic expression of CDK4 in these cells partially alleviated the growth defect. Thus CDK4 provides a direct link between the oncogenic effects of c-MYC and cell cycle regulation.