The goal of this review is to stress the importance of the cytochrome P450 (CYP) superfamily that is expressed in human skin in the hope that it may stimulate further study in an intriguing topic that currently suffers from a relative dearth of information. Like the cells that line the respiratory and GI tracts [X. Ding, L.S. Kaminsky, Human extrahepatic cytochromes P450: function in xenobiotic metabolism and tissue-selective chemical toxicity in the respiratory and gastrointestinal tracts, Annu. Rev. Pharmacol. Toxicol. 43 (2003) 149-173] those present in human skin express a variety of CYPs that play important roles in xenobiotic, drug and steroid metabolism. In addition, a few CYPs, with potentially novel roles in metabolism and keratinocyte function, have recently been discovered that appear to be expressed in a keratinocyte-specific manner [L. Du, S.M. Hoffman, D.S. Keeney, Epidermal CYP2 family cytochromes P450, Toxicol. Appl. Pharmacol. 195 (2004) 278-287]. However, in preparing this review, it soon became apparent that in contrast to the progress made in understanding these events in the liver, relatively little is known in the human skin. Thus, while a number of tantalizing stories are beginning to emerge, they are far from complete. In this review, a brief synopsis of the structure of skin and methods of culturing keratinocytes will be presented. This will be followed by an overview of the various CYPs and their putative regulators that have been currently identified to be expressed in human keratinocytes. Then, a more detailed analysis of CYP regulation that involves the aryl hydrocarbon receptor (AHR) signaling pathway will be offered in the hope that it may serve as a paradigm for other CYP regulatory studies in the skin. Finally, several clinical implications that may arise due to altered regulation of CYPs will be considered.