Epidermal differentiation is a continuous process, constituting and renewing a protective layer at the skin surface: the stratum corneum, composed of cornified keratinocytes that is a barrier to water diffusion. Massive loss of physiologic liquids is one of the severest consequences of extensive burns. The stratum corneum also protects the subjacent tissues from xenobiotic aggression, ultraviolet radiation (70 p. cent of UVB absorption) and from mechanic aggression. The integrity of the stratum corneum depends on three elements: 1) the physico-chemical quality of the cornified cells, 2) the persistence of mechanical junctions uniting these cells and 3) the organization and composition of the lipid "mortar" in the intercellular spaces. Since all these components are issued from the keratinocyte differentiation process, any perturbation may, in time, induce modifications in the "barrier" function of the epidermis. The barrier quality varies, depending on its localization (soles of the feet, palms of the hands and transitional epidermis of the lips), during skin healing (priority to keratinocyte proliferation to the detriment of maturation) under the influence of treatment (retinoids, vitamin D derivatives), in the course of aging and diseases: ichtyosis and other keratinization genodermatoses, benign (including psoriasis) and malignant hyperproliferative diseases. Furthermore, the relative impermeability of the stratum corneum is an important factor limiting the penetration and diffusion of allergens, but also local drugs delivered with local and systemic trans-epidermal treatments. Further knowledge is required on the function of the epidermal barrier and the mechanism regulating cohesion/desquamation of the stratum corneum to understand certain hereditary diseases, improve efficacy of topical therapeutic products and optimize cosmetic formulations.