The water permeability barrier of the stratum corneum (SC) seems primarily to be regulated by the lamellarly arranged lipid bilayers between the corneocytes, which originate largely from polar lipid precursors provided by the cells of stratum granulosum via exocytosis of the lamellar body (LB) content. In particular, the structural organization of these intercellular lipid lamellae seems to be responsible for the very low water permeability of the intact skin, and these lipid-rich structures might also influence the desquamation process in the SC. The aim of this study was to obtain further insight into the distribution and organization of the epidermal lipids (EL) and the mechanism involved in desquamation and barrier function in normal human skin and scaling skin disorders. Biopsies of healthy human skin (n = 12), of inflammatory skin diseases (atopic dry skin (n = 9), psoriatic skin lesions [n = 2]), and of hereditary keratinization disorders (autosomal recessive ichthyoses congenita (n = 3), X-chromosomal ichthyosis (XCI) [n = 3]) were analyzed utilizing a special fixation protocol with ruthenium tetroxide (RuO4) postfixation. While the atopic dry skin revealed normal barrier structures, the psoriasis lesions were characterized by severe alteration of the lipid structures leading to an abnormal interaction with the desmosomal unit. While the intercellular domains in some of the studied keratinization disorders showed an impaired distribution of the EL (autosomal recessive ichthyoses), X-chromosomal ichthyosis showed normal lipid architecture. Dry and scaly skin disorders are therefore not always accompanied by an impairment of the water permeability barrier