The SCAN domain is a highly conserved dimerization motif that is vertebrate-specific and found near the N-terminus of C(2)H(2) zinc finger proteins (SCAN-ZFP). Although the function of most SCAN-ZFPs is unknown, some have been implicated in the transcriptional regulation of growth factors, genes involved in lipid metabolism, as well as other genes involved in cell survival and differentiation. Here we utilize a bioinformatics approach to define the structures and gene locations of the 71 members of the human SCAN domain family, as well as to assess the conserved syntenic segments in the mouse genome and identify potential orthologs. The genes encoding SCAN domains are clustered, often in tandem arrays, in both the human and mouse genomes and are capable of generating isoforms that may affect the function of family members. Twenty-three members of the mouse SCAN family appear to be orthologous with human family members, and human-specific cluster expansions were observed. Remarkably, the SCAN domains in lower vertebrates are not associated with C(2)H(2) zinc finger genes, but are contained in large retrovirus-like polyproteins. Collectively, these studies define a large family of vertebrate-specific transcriptional regulators that may have rapidly expanded during recent evolution.