The skin forms a barrier to the external environment, maintaining body fluids within our system and excluding harmful substances, while the skin is a site of administration of drugs for topical and systemic chemotherapy. It is an important issue to predict the rate at which drugs or other xenobiotics penetrate the skin. In this article, we review modeling approaches for predicting skin permeation of compounds, including both mechanistic and empirical approaches. Mechanistic approaches can give us much information on understanding of skin permeation of the compounds, such as structure-permeability relationship, contribution of each barrier step, mechanism of penetration enhancers, and in vivo-in vitro relationship. On the other hand, empirical modeling can overcome any inaccuracies of mechanistic models caused by the existence of uncertainties and, therefore, give us better predictions from the practical point of view. Artificial neural networks are being available for empirical modeling of complex skin transport phenomenon.