Skin, being the largest organ of the body, represents an important route of exposure, not only for the abundance of chemicals present in the environment, but also for products designed for topical application such as drugs and personal care products. Determining whether such incidental or intentional exposure poses a risk to human health requires consideration of temporal concentration, both externally and internally, in addition to assessing the chemical’s intrinsic hazard. In order to elicit a toxic response in vivo the chemical must reach its site of action in sufficient concentration, as determined by its absorption, distribution, metabolism and elimination (ADME) profile. Whilst absorption and distribution into and through skin layers have been studied for decades, only more recently has skin metabolism become a subject of intense research, now recognised as playing a key role in both toxification and detoxification processes. The majority of information on metabolic processes, however, has generally been acquired via studies performed on the liver. This paper outlines strategies that may be used to leverage current knowledge, gained from liver metabolism studies, to inform predictions for skin metabolism through understanding the differences in the enzymatic landscapes between skin and liver. The strategies outlined demonstrate how an array of in silico tools may be used in concert to resolve a significant challenge in predicting toxicity following dermal exposure. The use of in vitro methods for determining skin metabolism, both to provide further experimental data for modelling and to verify predictions is also discussed. Herein, information on skin metabolism is placed within the context of toxicity prediction for risk assessment, which requires consideration of both exposure and hazard of parent chemicals and their metabolites.