Substrate-specific degradation is a key feature of the ubiquitin proteasome system. Substrate specificity is typically directed by the E3 or ubiquitin ligase; such specificity can be conferred either by ligase modification or expression or conversely via modification of substrates that permit their recognition by a specific E3 ligase. The most well-known example of such complexes are the Cullin-RING ligases (CRLs). CRLs are composed of one of seven cullin-family scaffold proteins; the CRL serves as a scaffold that interacts directly with a RING-domain enzyme (Rbx1/2) through an extensive protein-protein interface within the globular C-terminal domain. At the N terminus, the cullin associates with an adaptor protein through cullin-repeat motifs. This adaptor, in turn, facilitates recruitment of a substrate-specifying factor that recruits the target to be ubiquitylated. The prototypical CRL is the cul1-containing complex, commonly referred to as the Skp1-Cul1-Fbox (SCF) ligase. SCF ligases contribute to the timely destruction of numerous substrates thereby ensuring normal cell growth. The importance of SCF function is highlighted by cancer-specific alterations in either the expression or the function of select F-box substrate-specific adaptors that results in neoplastic conversion. Herein, we discuss the current understanding of SCF function and contribution to cell biology.