S-antigen has been considered a specific protein of photoreactive cells by immunohistochemical criteria. It was observed in the retina and pineal gland of all examined vertebrates as well as in photoreceptors of invertebrates, but not currently in other organs. However, contrary to pineal cells of poikilotherms and birds which are true or modified photoreceptors, mammalian pinealocytes are not photosensitive. Recent experiments demonstrated that S-antigen-like proteins are present in low amount in many other cells in the body. These proteins are characterized by the same migration pattern (the same molecular weight) as retinal S-antigen in SDS-electrophoresis and by their immuno-reactivity with a panel of monoclonal and polyclonal antibodies to S-antigen. These cells are not photosensitive, but are controlled byβadrenergic, G-protein mediated adenylate cyclase system, a transduction system that shares many structural and functional homologies with visual transduction. S-antigen (arrestin) plays a regulatory role in phototransduction in rods by desensitizing rhodopsin. In the mammalian pineal and in other cells or tissues, S-antigen, or a family of structurally related proteins, could similarly be involved in the regulation of chemical signal transduction. Whether any systemic pathology is associated with uveoretinitis and pinealitis after S-antigen immunization deserves further investigations.