A20 is a ubiquitin-editing molecule. It belongs to a novel family of deubiquitinating cysteine proteases, called the ovarian tumor (OTU) family, which can cleave monoubiquitin from modified proteins. In addition, A20 contains seven Cys2-Cys2 zinc fingers, one of which is believed to regulate E3 ubiquitin ligase activity. Here we review the biology of human genes that encode OTU domains or contain A20-type zinc fingers. The human genome contains 15 members of the OTU family including the deubiquitinating enzymes Cezanne, VCIP135 and Otubain 1. Genomic analysis also identified 10 genes that contain A20-type zinc fingers including Rabex5, Znf216 and AWP1. In Rabex5 the A20-zinc finger regulates E3 ligase activity whereas A20-type zinc fingers of Znf216 and AWP1 function as ubiquitin-binding motifs. A20 and its relatives regulate highly divergent physiological activities including NF-κB activity (A20, Cezanne, Znf216, Rabex5), endocytosis (Rabex5, AWP1), skeletal muscle atrophy (Znf216), Golgi membrane fusion (VCIP135) and T cell anergy (Otubain 1). Further studies are required to characterize the biology of other A20-related molecules whose function remains largely undefined.