Human skin contains several proteins that could bind the hydrophobic retinoids. One is retinol-binding protein (RBP), the plasma carrier of natural vitamin A, retinol, albumin, and two specific cellular-binding proteins, one for retinol (CRBP) and one for retinoic acid (CRABP). Adequate techniques for the study of these proteins in human skin have been developed; this was considered a necessary step in the understanding of how natural and synthetic retinoids work in the skin. A polyacrylamide gel electrophoresis technique followed by protein immunoblot analysis with an antiserum specific against RBP was developed. This technique allowed study of the binding of several natural and synthetic retinoids on the plasma carrier of natural vitamin A for the first time; it was found that only natural retinoids, including retinoic acid, bind to RBP in vitro; retinoic acid binding was found to induce major conformational changes in the protein. Isotretinoin did not bind to RBP. The technique was then used for the study of RBP in human epidermal and dermal extracts; it showed that RBP degradation with loss of binding properties for retinol occurred within the epidermis; this suggests that retinol supply is decreased within the epidermis, a fact that could be linked to cornification. A polyacrylamide gel electrophoresis binding assay was developed for studying CRBPs and CRABPs in human skin cytosolic extracts. This assay is more specific and more convenient than previous ones for studying tissue extracts. The CRABP was (1) in much higher levels in normal epidermis than in normal dermis, (2) dramatically elevated in psoriatic plaques and in some retinoid-responsive dermatoses, and (3) up modulated by both topical and systemic administration of natural and synthetic retinoids. Such alterations were not observed for CRBP. From these and other observations reviewed herein, it seems that CRABP should be one of the first candidates to be carefully analyzed in the search of the cellular receptor for the mediation of the synthetic retinoids in pharmacologic effects in human skin.