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The protective function of skin (its low permeability) presents a formidable obstacle in therapeutical applications such as transdermal drug delivery and gene delivery in skin. One of the possibilities to temporarily breach the barrier function of skin is using electroporation, creating aqueous pathways across lipid-based structures by means of electric pulses. In addition, the application of electric pulses to biological cells causes the electroporation of cell membrane, increasing its permeability, thus enabling cell uptake of larger molecules that otherwise cannot cross the membrane, such as drug molecules or DNA. The electropermeabilization process in skin was described theoretically, by means of numerical modeling, leaning on data derived from our in vivo experiments previously published. The numerical models took into account the layered structure of skin, macroscopical changes of its bulk electrical properties during electroporation, as well as the presence of localized sites of increased molecular transport termed local transport regions. The output of the models was compared with the in vivo experiments, and a good agreement was obtained. In addition, a comparison of our results with already published findings on skin electropermeabilization showed that permeabilizing voltage amplitudes suggested by the model are also well in the range of the voltage amplitudes reported by other authors to cause skin permeabilization. The subject of tissue conductivity changes due to electroporation is still a rather unexplored field; however, we used the available data to describe the mechanism of the nonlinear process of the tissue electropermeabilization.