The eukaryotic cell cycle is regulated by the sequential activation of cyclin-dependent kinases (CDKs). CDK activation is regulated by phosphorylation of the catalytic subunit, by binding to activating (cyclins) and inactivating subunits (cyclin-dependent kinase inhibitor). In this review, we will focus on the role of the cyclin-dependent kinase inhibitor p27 which has been recently the subject of extensive work. This negative regulator of cell growth indeed illustrates the pleiotropic biological effects of such molecules in both normal and cancer cells and the complexity of the regulatory mechanisms involved.