Much of the targeted protein ubiquitylation that occurs in eukaryotes is performed by cullin-based E3 ubiquitin ligases, which form a superfamily of modular E3s. The best understood cullin-based E3 is the SCF ubiquitin ligase (Feldman et al. 1997; Skowyra et al. 1997), which is composed of a modular E3 core containing CUL1 and RBX1 (also called ROC1), and a substrate specificity module composed of SKP1 and a member of the F-box family of proteins (Cardozo and Pagano 2004). The CUL1/RBX1 complex functions as a scaffold to assemble the E2 ubiquitin conjugating enzyme with the substrate specificity module (Zheng et al. 2002). CUL1 interacts with RBX1 through its C terminus and with SKP1 through its N terminus. The interaction of F-box proteins with SKP1 occurs through the F-box motif, an∼ 40-amino acid motif first identified in budding yeast Cdc4p and human cyclin F, the latter giving the name to the entire family (Bai et al. 1996). F-box proteins contain additional protein interaction domains that bind ubiquitylation targets. The overall architecture of SCF complexes is conserved in the superfamily of SCF-like ubiquitin ligases that use cullin proteins as a scaffold. All cullins characterized to date (CUL1–5) are known to interact with RBX1 or RBX2 but use distinct specificity modules, which generally display structural and functional similarities with the SKP1/F-box protein module. For example, CUL2 and CUL5 are known to interact with the SKP1-like protein elongin C, which, in turn, interacts with F-box protein-like specificity factors called BC/SOCS-box proteins (Deshaies 1999; Guardavaccaro and Pagano 2003). In addition, CUL3 interacts with the BTB/POZ family of proteins, which appear to merge the functions of SKP1 and the F-box protein into a single polypeptide (Furukawa et al. 2003; Geyer et al. 2003; Pintard et al. 2003; Xu et al. 2003), with the BTB domain displaying structural relationships with SKP1 (Schulman et al. 2000; Xu et al. 2003). Cul4 forms a complex wherein DDB1/DDB2 and CSA proteins appear to function as substrate specificity modules (Groisman et al. 2003). Thus, the current expectation is that all cullincontaining ligases will share the modular nature of the original SCF family of ligases. A major strategy employed by the SCF is the use of extended protein families as specificity factors. In 1999, we reported the identification of 47 F-box proteins in mammals (Cenciarelli et al. 1999; Winston et al. 1999). These proteins fell into three major classes, depending on the types of substrate interaction domains identified in addition to the F-box motif. The two largest classes of interaction domains are WD40 repeats (Smith et al. 1999) and leucine-rich repeats (LRRs)(Kobe and Kajava 2001). A third generic class of F-box proteins contained various other types of protein interaction domains or no recognizable domains. These classes of F-box proteins were designated FBWs, FBLs, and FBXs, respectively, followed by a numerical identifier (Cenciarelli et al. 1999; Winston et al. 1999). Paralogous genes in the same species used the same number followed by a letter (a, b,…) representing the individual genes in the paralogous group. The Human Genome Organization (HUGO) Gene Nomenclature Committee adopted a related four-letter gene nomenclature: FBXW, FBXL, and FBXO, respectively, where “O” in FBXO refers to “other” domains. Since this initial work, subsequent efforts, particularly cDNA and genomic sequencing projects, have facilitated the further identification of F-box protein-coding genes. However, the inconsistent use of nomenclature standards has greatly limited the utility of the sequence database. This inconsistency is …