The transition from G(1), phase to S phase of the mammalian cell cycle is controlled by many positive and negative regulators, among which cyclin E and p27(Kip1) respectively, undergo the most marked changes in concentration at this transition. The abundance of both cyclin E and p27(Kip1) is regulated predominantly by posttranslational mechanisms, in particular by proteolysis mediated by the ubiquitin-proteasome pathway. Cyclin E and p27(Kip1) each bind to and undergo polyubiquitination by the same ubiquitin ligase, known as SCFSkp2. The degradation of cyclin E and p27(Kip1) is greatly impaired in Skp2-deficient mice, resulting in intracellular accumulation of these proteins. In this article, recent progress in characterization of the molecular mechanisms that control the proteolysis of cyclin E and p27(Kip1) is reviewed.