New techniques for the analysis of proteins with specific binding for natural retinoids in human plasma and skin extracts have been developed. Polyacrylamide gel electrophoresis (PAGE), followed by protein blotting with an antiserum specific to retinol-binding protein (RBP), the plasma carrier of retinol, showed that: (1) retinoic acid induced striking conformational changes when bound to RBP, and (2) none of the several synthetic retinoids used in human therapy were found to bind to RBP. This directly confirms and extends previous indirect observations that synthetic retinoids are not delivered to the target organs through RBP. Human skin extracts incubated with either [3H]retinol or [3H]retinoic acid and analyzed by PAGE is a novel technique for the study of cellular retinol-(CRBP) and retinoic acid-(CRABP) binding proteins; it allows one to more specifically analyse these binding proteins and differentiate them from RBP. This technique confirmed and extended our previous observations: (1) CRABP is present in much higher amounts in the epidermis than in the dermis, whereas CRBP is detectable in very low amounts in both tissues, (2) a dramatic increase of CRABP is found in psoriatic plaques and (3) there is an up-modulation of epidermal CRABP during systemic or topical synthetic retinoid therapy. When the ability of some synthetic analogs of retinoic acid to compete with [3H]retinoic acid binding on human skin CRABP was studied, two important observations were made: (1) the analogs that, when given to human subjects were pharmacologically active, were found to be good competitors and vice-versa, (2) no strict correlation was found between the IC50 and the pharmacological potency of the retinoid.