A cDNA clone, encoding for a major component of the cornified cell envelope now termed loricrin, was isolated by cross-hybridization with the end domains of keratin 1 and 10. Loricrin is expressed very late in terminal epidermal differentiation in the upper stratum granulosum and is identical to the sulfur-rich component of the single type keratohyaline granule. Moreover, loricrin appears later to become cross-linked by the formation of glutamyl-lysyl-isopeptide bonds and thereby incorporated as a major component into the cornified cell envelope. In vivo, loricrin is expressed in all mammalian stratified epithelia tested so far. However, the highest levels of expression are found in humid tissues such as newborn epidermis, the epithelia of oral and anal mucosa, esophagus, foreskin, vagina and the epidermal parts of sweat ducts.