The B-box gene family represents a large number of genes involved in functions such as axial patterning, growth control, differentiation, and transcriptional regulation. These genes possess several conserved motifs that always include a B-box zinc binding motif associated with various other motifs such as the RING zinc finger, an alpha-helical coiled-coil, the rfp or B30.2 motif, propeller domain, and the NHL motif in various combinations. Mutations or rearrangements in several B-box family members are associated with human diseases and cancers such as familial Mediterranean fever (FMF), Optiz/BBB syndrome, acute promyelocytic leukemia, mulibrey nanism, and thyroid carcinomas. This suggests that members of this gene family play important roles in fundamental biological processes. Here we discuss the known members of this rapidly expanding protein family.