NAD(P)H is the major carrier of reducing equivalents in cells. NAD(P)‐dependent dehydrogenases and reductases catalyze the reversible transfer of hydrogen equivalents between substrates and NAD(P). These enzymes include alcohol dehydrogenases, 2‐hydroxyacid dehydrogenases, aldehyde dehydrogenases, amino acid dehydrogenases, secondary amine dehydrogenases, disulfide oxidoreductases, transhydrogenases, azoreductases, sulfite and nitrite reductases, and phosphite dehydrogenase. NAD(P)‐dependent dehydrogenases are structurally diverse, but many contain a Rossmann fold for NAD(P) binding. Usually, alcohol dehydrogenases contain an essential metal ion cofactor that serves as a Lewis acid for substrate activation. However, most dehydrogenases use general acid/base catalysis to activate substrates for reaction. NAD(P)‐dependent dehydrogenases have been used in biocatalysis for stereoselective reductions of ketones and imines to give chiral alcohols and amines, respectively. Several important drug targets (e.g., dihydrofolate reductase) are NAD(P)‐dependent dehydrogenases.