In order to address the problem of the elucidation of overall valid transdermal transport mechanisms, the permeation data on 20 amino acids and on the tetrapeptide hisetal as well as other literature data about skin permeation were analyzed in the present study. In addition, the iontophoretic as well as passive transport of the tetrapeptide hisetal across human skin was studied using Franz cells. The anode was placed in the side of the diffusion cell facing the epidermis and the cathode in the acceptor compartment. Current densities of 0.5 and 1 mA were applied. After 12 h of passive permeation maximally 1.2 μg hisetal was found in the acceptor compartment. After 2 h of iontophoretic delivery applying a constant current of 0.5 mA, 18.8 μg hisetal was detected while the application of a constant current of 1 mA for 2 h resulted in 28.7 μg hisetal in the acceptor compartment. Consequently, iontophoretic treatment increased the permeation rate of hisetal by a factor of 30. In comparison to the use of enhancers, iontophoretic treatment is much more effective. Facilitated permeation by enhancer treatment increased the permeation rate of hisetal across human skin maximally by a factor of 6. The results of the analysis of literature data, of our previous work on amino acids and the tetrapeptide hisetal, and of the present iontophoretic study show that the skin does not act as a simple lipoid barrier. The observation that increasing hydrophobicity did not correlate with increasing permeability of these amino acids as well as the finding that no relationship between the molecular weights of the amino acids and the peptide was observable led to the conclusion that amino acids and peptides appear to use another pathway through the skin. These findings and the fact that iontophoretic treatment is much more effective than enhancer treatment clearly seem to indicate that amino acids and the peptide permeate the skin mainly through water filled pores.