The skin permeation, Kp, of a chemical compound is a relevant parameter in fields such as toxicology, exposure to pollutants, or dermal studies of pharmaceutical and cosmetic interest. Nonetheless, its experimental determination is not a trivial task, and for this reason alternative methods to estimate Kp have been developed.This work evaluates the suitability of different methodologies to estimate skin permeation of neutral compounds. Three different approaches have been examined: estimation through the skin-PAMPA (Parallel Artificial Membrane Permeability Assay) permeability, Pe, estimation through the chromatographic retention factor combined with molecular volume, and finally estimation through a quantitative structure–property relationship (QSPR) based on the octanol–water partition coefficient, log Po/w, and molecular volume as descriptors. The three approaches have been tested with the same set of compounds and it has been observed that all of them can be used to estimate Kp with similar results, although the chromatographic method presents slightly improved statistics in addition to the facility of measurement.As many drugs are partially ionised at the pH of skin, the influence of pH in skin-PAMPA permeability has been also studied. To this end, the log Pe vs. pH profiles of a set of 25 compounds of different nature have been determined. As expected, the permeation of neutral forms is higher than the one of ionic forms, and permeation of neutral and ionic species are not governed by the same mechanisms.