Over the past few years, a growing body of evidence has brought to light critical roles for ubiquitin-dependent protein degradation in controlling the cellular levels of a large variety of proteins such as cyclins, cyclin-dependent kinase inhibitors, oncogenes, and tumor suppressors, which play integral roles in regulation of cell growth. Ubiquitin-dependent protein degradation is a complex, multistep process that proceeds with the tagging of target proteins with a poly-ubiquitin chain and culminates with the processive, ubiquitin- dependent degradation of tagged proteins by the 26S proteasome (Hershko et al. 1983; Hochstrasser 1995, 1996; Hershko and Ciechanover 1998). In the first step, the C-terminus of ubiquitin is covalently linked through a thioester bond to the active site cysteine residue of an El ubiquitin-activating enzyme. Ubiquitin is then transferred from the El via a thioester linkage to an active site cysteine residue in one of a number of E2 ubiquitin-conjugating enzymes. Ubiquitin is then either (1) conjugated directly via an isopeptide bond to the 8-amino group of a lysine in the target protein, (2) conjugated via an isopeptide bond to another ubiquitin moiety on the target protein as part of synthesis of the poly-ubiquitin tag, or (3) transferred from the E2 via a thioester bond to an active site cysteine residue in one of a growing family of E3 ubiquitin ligases, which then conjugate ubiquitin to specific target proteins.