Based on the structure of the Stratum corneum (SC) the potential penetration/diffusion pathways of drugs and cosmetic actives through the SC are presented and discussed. The well-known lipophilic pathway across the SC is presented and relevant examples are used to show that highly lipophilic molecules such as glucocorticoids, coenzyme Q10 etc. are accumulated in the SC and penetrate into the inner liquid like layer of the SC lipid bilayer by lateral diffusion. The diffusion into and across the SC of highly hydrophilic drugs and active substances such as urea, amino acids and peptides is still under discussion. Another diffusion pathway for the highly hydrophilic molecules via the corneocytes and the corneodesmosomes is presented and discussed, the corneocytary diffusion pathway.