The eukaryotic cell cycle consists of a series of sequential phases, the order of which is highly regulated to ensure the faithful transmission of intact genome equivalents to daughter cells. Progression through the cell cycle depends on the activity of cyclin-dependent kinases (Cdks), which drive the transitions between phases by targeting numerous, but largely unknown, substrates for phosphorylation. The activity of Cdks is subject to both positive and negative regulation by their temporal association with cyclins and Cdk inhibitors, respectively. Whereas Cdks are constitutively expressed throughout the cell cycle, the levels of cyclins and Cdk inhibitors are regulated by both transcriptional and post-transcriptional processes. The discovery that many cyclins and Cdk inhibitors are unstable proteins has implicated regulated protein degradation as a critical mechanism in cell cycle control. Proteolysis allows for the rapid removal of cell cycle regulators promoting irreversible transitions between cell cycle phases. The rapid removal of positive regulators prevents them from interfering with regulation of subsequent cell cycle events. In this review, we highlight the recent advances of our understanding of how a recently discovered ubiquitin ligase, designated SCF, contributes to mammalian cell cycle control.