Reduced levels of the cyclin dependent kinase inhibitor p27Kip1 connote poor prognosis in cancer. In human Burkitt lymphoma, and in pre-cancerous B cells and lymphomas arising in Eμ-Myc transgenic mice, p27Kip1 expression is markedly reduced. Furthermore, the Cks1 component of the SCFSkp2 complex that is necessary for p27Kip1 ubiquitylation and degradation, and to a lesser extent Skp2, are induced by Myc ex vivo and in Eμ-Myc B-cells and lymphomas, and up-regulation of CKS1 and SKP2 are hallmarks of Burkitt lymphoma. While loss of Skp2 has rather modest effects, the deletion of Cks1 in Eμ-Myc B-cells elevates p27Kip1 levels, reduces proliferation and delays lymphoma development. In contrast, Myc-induced apoptosis and transcriptional activity are not affected by Cks1 (or Skp2) loss. Therefore, Myc accelerates cell proliferation and promotes tumorigenesis through its ability to selectively induce Cks1.