The proliferation of a few antigen-reactive lymphocytes into a large population of effector cells is a fundamental property of adaptive immunity. The cell division that fuels this process is driven by signals from antigen, co-stimulatory molecules and growth factor receptors, and is controlled by the cyclin-dependent kinase (CDK) cascade. In this Opinion article, we discuss how the CDK cascade provides one potential link between cell division and differentiation through the phosphorylation of immunologically relevant transcription factors, and how components of this pathway might ultimately participate in the decision between tolerance and immunity.