Carbonyl groups are frequently found in endogenous or xenobiotic compounds. Reactive carbonyls, formed during lipid peroxidation or food processing, and xenobiotic quinones are able to covalently modify DNA or amino acids. They can also promote oxidative stress, the products of which are thought to be an important initiating factor in degenerative diseases or cancer. Carbonyl groups are reduced by an array of distinct NADPH-dependent enzymes, belonging to several oxidoreductase families. These reductases often show broad and overlapping substrate specificities and some well-characterized members, e.g., carbonyl reductase (CBR1) or NADPH-quinone reductase (NQO1) have protective roles toward xenobiotic carbonyls and quinones because metabolic reduction leads to less toxic products, which can be further metabolized and excreted. This review summarizes the current knowledge on structure and function relationships of the major human and mammalian carbonyl reductases identified.