The water permeability of the stratum corneum (SC) appears to be regulated primarily by the lamellar arrangement of lipid bilayers between the corneocytes. A significant body of evidence already exists, suggesting that the specific structural organization of these intercellular lipid lamellae is responsible for the very low water permeability of the intact skin and that these lipid-rich structures may also influence the process of desquamation in the SC. In this electron microscopic study the structure of the intercellular domains at different levels within the SC of normal skin from 18 healthy subjects has been evaluated with a special fixation protocol utilizing acrolein vapour as primary fixation, followed by a modified ruthenium tetroxide (RuO4)-post-fixation technique. This procedure permitted an insight into the process of post-secretory extracellular processing of the lamellar body (LB)-derived lipids into lamellar lipid bilayers. This transformation takes place in unique saccular invaginations of the intercellular domains, which indent the underlying stratum granulosum (SG) cells. In this specialized environment LB lipids arc first processed into broad sheets before they become part of the typical lamellar lipid structure of the SC. Furthermore. in the process of lipid maturation distinct differences between inner and outer parts of the SC emerge, in particular an increase in both the number of the lamellae per intercellular space, and their order of arrangement. Moreover, distinct structural relationships between desmosomes (at the SG/SC interface and lower SC) and desmosomal remnants (at the stratum disjunctum) on the one hand, and lipid layers on the other, have been demonstrated, pointing to an important functional interaction of these components in normal human skin.