The present study demonstrated that Cdk4 disruption completely inhibited pituitary and islet tumorigenesis in Men1+/− mice. This is in contrast with the finding that Cdk2 disruption did not affect pituitary and islet tumorigenesis. Cdk4 deficiency markedly inhibited islet proliferation in both wild-type and Men1+/− mice, while Cdk2 deficiency showed no appreciable effects. LOH at the Men1 locus was observed in Cdk-wild type or Cdk2-null pituitary tumors, whereas no sign of LOH was detected in Cdk4-null pituitaries. These observations suggest that CDK4 plays a unique and essential role in islet and pituitary tumorigenesis initiated by the loss of menin.