A variety of carbonyl compounds are present in foods, environmental pollutants, and drugs. These xenobiotic carbonyl compounds are metabolized into the corresponding alcohols by many mammalian NAD(P)H-dependent reductases, which belong to the short-chain dehydrogenase/reductase (SDR) and aldo-keto reductase superfamilies. Recent genomic analysis, cDNA isolation and characterization of the recombinant enzymes suggested that, in humans, the six members of each of the two superfamilies, i.e., total of 12 enzymes, are involved in the reductive metabolism of xenobiotic carbonyl compounds. They comprise three types of carbonyl reductase, dehydrogenase/reductase (SDR family) member 4, 11beta-hydroxysteroid dehydrogenase type 1, L-xylulose reductase, two types of aflatoxin B1 aldehyde reductase, 20alpha-hydroxysteroid dehydrogenase, and three types of 3alpha-hydroxysteroid dehydrogenase. Accumulating data on the human enzymes provide new insights into their roles in cellular and molecular reactions including xenobiotic metabolism. On the other hand, mice and rats lack the gene for a protein corresponding to human 3alpha-hydroxysteroid dehydrogenase type 3, but instead possess additional five or six genes encoding proteins that are structurally related to human hydroxysteroid dehydrogenases. Characterization of the additional enzymes suggested their involvement in species-specific biological events and species differences in the metabolism of xenobiotic carbonyl compounds.