This review presents comparative aspects of epidermal keratinization in vertebrates, with emphasis on the evolution of the stratum corneum in land vertebrates. The epidermis of fish does not contain proteins connected with interkeratin matrix and corneous cell envelope formation. Mucus-like material glues loose keratin filaments. In amphibians a cell corneous envelope forms but matrix proteins, aside from mucus/glycoproteins, are scarce or absent. In reptiles, birds, and mammals specific proteins associated with keratin become relevant for the production of a resistant corneous layer. In reptiles some matrix, histidine-rich and sulfur-rich corneous cell envelope proteins are produced in the soft epidermis. In avian soft epidermis low levels of matrix and cornified proteins are present while lipids become abundant. In mammalian keratinocytes, interkeratin proteins, cornified cell envelope proteins, and transglutaminase are present. Topographically localized areas of dermal-epidermal interactions in amniote skin determine the formation of skin derivatives such as scales, feathers, and hairs. New types of keratin and associated proteins are produced in these derivatives. In reptiles and birds beta-keratins form the hard corneous material of scales, claws, beaks, and feathers. In mammals, small sulfur-rich and glycine-tyrosine-rich proteins form the corneous material of hairs, horns, hooves, and claws. Molecular studies on reptilian beta-keratins show they are glycine-rich proteins. They have C- and N-terminal amino acid regions homologous to those of mammalian proteins and a central core with homology to avian scale/feather keratins. These findings suggest that ancient reptiles already possessed some common genes that later diversified to produce some keratin-associated protein in extant reptiles and birds, and others in mammals. The evolution of these small proteins represents the more recent variation of the process of cornification in vertebrates.