The cell-cycle kinase CDK6 has been recognized not only as a typical cyclin-dependent kinase but as a transcriptional regulator with properties distinct from those of its close homologue CDK4. CDK6 regulates the transcription of a number of genes and its effects may be dependent on or independent of its kinase activity. The transcriptional function of CDK6 is crucial for its role in promoting myeloid and lymphoid malignancies, including AML and ALL and is important in maintaining hematopoietic and leukemic stem cells. CDK6 contributes to tumor formation by regulating transcriptional responses in a stage-specific manner. In early stages CDK6 kinase induces a complex transcriptional program to block p53 in hematopoietic cells. Cells lacking CDK6 kinase function are required to mutate p53 to achieve a fully transformed immortalized state. CDK6 binds to the promoters of genes including the p53-antagonists PRMT5, PPM1D and MDM4.