Published permeability coefficient (K p) data for the transport of a large group of compounds through mammalian epidermis were analyzed by a simple model based upon permeant size [molecular volume (MV) or molecular weight (MW)] and octanol/water partition coefficient (K oct). The analysis presented is a facile means to predict the percutaneous flux of pharmacological and toxic compounds solely on the basis of their physicochemical properties. Furthermore, the derived parameters of the model have assignable biophysical significance, and they provide insight into the mechanism of molecular transport through the stratum corneum (SC). For the very diverse group of chemicals considered, the results demonstrate that SC intercellular lipid properties alone are sufficient to account for the dependence of K p upon MV (or MW) and K oct. It is found that the existence of an “aqueous-polar (pore) pathway” across the SC is not necessary to explain the K p values of small, polar nonelectrolytes. Rather, their small size, and consequently high diffusivity, accounts for their apparently larger-than-expected K p. Finally, despite the size and breadth of the data set (more than 90 compounds with MW ranging from 18 to >750, and log K oct ranging from −3 to + 6), the postulated upper limiting value of K p for permeants of very high lipophilicity cannot be determined. However, the analysis is able to define the physicochemical characteristics of molecules which should exhibit these maximal K p values. Overall, then, we present a facile interpretation of a considerable body of skin permeability measurements that (a) very adequately describes the dependence of K p upon permeant size and lipophilicity, (b) generates parameters of considerable physicochemical and mechanistic relevance, and (c) implies that the SC lipids alone can fully characterize the barrier properties of mammalian skin.