Aldo-keto reductases (AKRs) are soluble NAD(P)(H) oxidoreductases that primarily reduce aldehydes and ketones to primary and secondary alcohols, respectively. The ten known human AKR enzymes can turnover a vast range of substrates, including drugs, carcinogens, and reactive aldehydes. They play central roles in the metabolism of these agents, and this can lead to either their bioactivation or detoxication. AKRs are Phase I drug metabolizing enzymes for a variety of carbonyl-containing drugs and are implicated in cancer chemotherapeutic drug resistance. They are involved in tobacco-carcinogenesis because they activate polycyclic aromatic trans-dihydrodiols to yield reactive and redox active o-quinones, but they also catalyze the detoxication of nicotine derived nitrosamino ketones. They also detoxify reactive aldehydes formed from exogenous toxicants, e.g., aflatoxin, endogenous toxicants, and those formed from the breakdown of lipid peroxides. AKRs are stress-regulated genes and play a central role in the cellular response to osmotic, electrophilic, and oxidative stress.