As reviewed in this article, the stratum corneum must now be accorded the respect due to a structurally heterogeneous tissue possessing a selected array of enzymatic activity. The sequestration of lipids to intercellular domains and their organization into a unique multilamellar system have broad implications for permeability barrier function, water retention, desquamation, and percutaneous drug delivery. Yet, the functions and organization of specific lipid species in this membrane system are still unknown. Certain novel insights have resulted from comparative studies in avians and marine mammals. Further elucidation of the molecular architecture and interactions of lipid and nonlipid components of the stratum corneum intercellular domains will be a prerequisite for a comprehensive understanding of stratum corneum function.