The mammalian skin has long been considered to be poor in drug metabolism. However, many reports clearly show that most drug metabolizing enzymes also occur in the mammalian skin albeit at relatively low specific activities. This review summarizes the current state of knowledge on drug metabolizing enzymes in the skin of human, rat, and pig, the latter, because it is often taken as a model for human skin on grounds of anatomical similarities. However only little is known about drug metabolizing enzymes in pig skin. Interestingly, some cytochromes P450 (CYP) have been observed in the rat skin which are not expressed in the rat liver, such as CYP 2B12 and CYP2D4. As far as investigated most drug metabolizing enzymes occur in the suprabasal (i.e. differentiating) layers of the epidermis, but the rat CYP1A1 rather in the basal layer and human UDP-glucuronosyltransferase rather in the stratum corneum. The pattern of drug metabolizing enzymes and their localization will impact not only the beneficial as well as detrimental properties of drugs for the skin but also dictate whether a drug reaches the blood flow unchanged or as activated or inactivated metabolite(s).