The aldo-keto reductases (AKRs) represent a growing oxidoreductase superfamily. Forty proteins have been identified and characterized as AKRs, and an additional fourteen genes may encode proteins related to the superfamily. Found in eukaryotes and prokaryotes, the AKRs metabolize a wide range of substrates, including aliphatic aldehydes, monosaccharides, steroids, prostaglandins, and xenobiotics. This broad substrate specificity has caused problems in naming these proteins. Enzymes capable of these reactions have been referred to as aldehyde reductase (ALR1), aldose reductase (ALR2), and carbonyl reductase (ALR3); however, ALR3 is not a member of the AKR superfamily. Also, some AKRs have multiple names based upon substrate specificity. For example, human 3alpha-hydroxysteroid dehydrogenase (3apha-HSD) type I is also known as dihydrodiol dehydrogenase 4 and chlordecone reductase. To address these issues, we propose a new nomenclature system for the AKR superfamily based on amino acid sequence identities. Cluster analysis of the AKRs shows seven distinct families at the 40% amino acid identity level. The largest family (AKR1) contains the aldose reductases, aldehyde reductases, and HSDs. Other families include the prokaryotic AKRs, the plant chalcone reductases, the Shaker channels, and the ethoxyquin-inducible aflatoxin B1 aldehyde reductase. At the level of 60% amino acid identity, subfamilies are discernible. For example, the AKR1 family includes five subfamilies: (A) aldehyde reductases (mammalian); (B) aldose reductases; (C) HSDs; (D) delta4-3-ketosteroid-5beta-reductases; and (E) aldehyde reductases (plant). This cluster analysis forms the basis for our nomenclature system. Recommendations for naming an aldo-keto reductase include the root symbol "AKR," an Arabic number designating the family, a letter indicating the subfamily when multiple subfamilies exist, and an Arabic numeral representing the unique protein sequence. For example, human aldehyde reductase would be assigned as AKR1A1. Our nomenclature is both systematic and expandable, thereby allowing assignment of consistent designations for newly identified members of the superfamily.