The removal and metabolism of organic molecules is apivotal body function, usually performed by phase I andphase II enzymes. While detoxification is beneficial andnecessary, at the same time, the metabolic intermediatesand breakdown products generated in the process can haveimmunogenic, cancerogenic or apoptogenic potential,which differs from the respective parental chemical.Whether and which adverse health effects ensue dependson the affected cell types and tissue. For instance, ifdamage caused by a chemical induces apoptosis, easilyregenerating tissues may cope better than slowly prolifer-ating or rare precursor cells. On the other hand, potentialextent of damage is conceivably dependent on the xeno-biotic metabolizing activity of cell types, which in turnmight be governed by exposure, that is, tissues with highexposure could be more competent in xenobiotic metabo-lism. There is, however, a surprising lack of research toidentify cell-specific xenobiotic metabolism. Research onthe molecular activity of xenobiotic metabolizing enzymes(XME) has traditionally a strong focus on the liver as themain metabolizing and detoxifying organ of the body. Theskin is less well studied, albeit it forms a major barrieragainst the environment (including the chemical environ-ment) and is a target of occupational, accidental andintended-use (i.e., cosmetics and pharmaceuticals) chemi-cal exposure. Risks of exposure are irritation, inflamma-tion, allergies and cancer. Conceivably, skin cells maypossess yet underestimated strategies to balance XME-mediated danger.In a recent paper, the team around Michael Girardi(Modi et al. 2012) presented the exciting finding that dif-ferential expression of phase I enzymes CYP4501A1 and1B1 in skin Langerhans cells versus keratinocytes leads togeneration of DNA-modifying metabolites from the car-cinogen 7,12-Dimethylbenz[a]anthracen (DMBA) in theskin and eventually non-melanoma skin cancer. Theyfound that skin Langerhans cells efficiently metabolizeDMBA to DMBA-3,4-diol which leads to oncogenic Hrasmutations. Mice lacking skin Langerhans cells had fewerskin tumours upon DMBA treatment. They conclude‘‘ Thus, tissue-associated dendritic cells can enhancechemical carcinogenesis via PAH metabolism, highlightingthe complex relation between immune cells and carcino-genesis.’’ While the paper of Girardi and colleagues looksat chemical-induced (DMBA-induced) cancer, it has alsoimportant implications for understanding skin physiologyand skin toxicology.Sun light, that is, its UV radiation component, is themost important stressor of skin (Fritsche et al. 2007) andhas long been known to be genotoxic and a major riskfactor in skin cancer (Narayanan et al. 2010). UV and UV-induced DNA damage are the primary cause not only formelanoma with increasing incidence and new casesworldwide every year (Little and Eide 2012), but also ofskin basal cell carcinoma, squamous cell carcinoma,Kaposi