A novel human opsin, melanopsin, has been identified and localized to the inner retina of mammals. The human melanopsin gene consists of 10 exons and is located on chromosome 10q22, differing significantly from other human opsins. Melanopsin is expressed exclusively in the eye, specifically in the ganglion and amacrine cell layers of the primate and murine retinas. Unlike retinal photoreceptors, melanopsin is not involved in image formation but may mediate nonvisual photoreceptive tasks, such as regulating circadian rhythms and suppressing pineal melatonin. The anatomical distribution of melanopsin-positive retinal cells resembles the pattern of cells projecting to the suprachiasmatic nuclei, a primary circadian pacemaker. Melanopsin shares greater sequence homology with invertebrate opsins than vertebrate opsins. It is more similar to the Gq-coupled opsin of the scallop than any known vertebrate opsin. The substitution of the acidic Schiff's base counterion in vertebrate opsins with an aromatic residue in invertebrate opsins suggests that melanopsin's photopigment-regenerating mechanism is more similar to that of invertebrates. This independence from auxiliary chromophore-regenerating tissues like the retinal pigment epithelium is a valuable attribute for nonvisual photoreceptors. The presence of melanopsin in the inner retina raises the possibility that some mammalian ganglion and amacrine cells are directly photosensitive. This is supported by findings that mice lacking rods and cones can still regulate circadian rhythms and pineal melatonin levels. Bilateral eye removal abolishes this regulation, suggesting the existence of nonrod, noncone photoreceptors in the mammalian eye. Melanopsin is one of four opsins expressed outside the photoreceptor layer in human and mouse retinas, including retinal G-protein-coupled receptor (RGR), peropsin, and encephalopsin. Melanopsin is uniquely expressed in the ganglion and amacrine cell layers of the retina, making it a viable candidate for a mammalian circadian photopigment. Its unique anatomical localization and known action spectra support its role in circadian photoreception.A novel human opsin, melanopsin, has been identified and localized to the inner retina of mammals. The human melanopsin gene consists of 10 exons and is located on chromosome 10q22, differing significantly from other human opsins. Melanopsin is expressed exclusively in the eye, specifically in the ganglion and amacrine cell layers of the primate and murine retinas. Unlike retinal photoreceptors, melanopsin is not involved in image formation but may mediate nonvisual photoreceptive tasks, such as regulating circadian rhythms and suppressing pineal melatonin. The anatomical distribution of melanopsin-positive retinal cells resembles the pattern of cells projecting to the suprachiasmatic nuclei, a primary circadian pacemaker. Melanopsin shares greater sequence homology with invertebrate opsins than vertebrate opsins. It is more similar to the Gq-coupled opsin of the scallop than any known vertebrate opsin. The substitution of the acidic Schiff's base counterion in vertebrate opsins with an aromatic residue in invertebrate opsins suggests that melanopsin's photopigment-regenerating mechanism is more similar to that of invertebrates. This independence from auxiliary chromophore-regenerating tissues like the retinal pigment epithelium is a valuable attribute for nonvisual photoreceptors. The presence of melanopsin in the inner retina raises the possibility that some mammalian ganglion and amacrine cells are directly photosensitive. This is supported by findings that mice lacking rods and cones can still regulate circadian rhythms and pineal melatonin levels. Bilateral eye removal abolishes this regulation, suggesting the existence of nonrod, noncone photoreceptors in the mammalian eye. Melanopsin is one of four opsins expressed outside the photoreceptor layer in human and mouse retinas, including retinal G-protein-coupled receptor (RGR), peropsin, and encephalopsin. Melanopsin is uniquely expressed in the ganglion and amacrine cell layers of the retina, making it a viable candidate for a mammalian circadian photopigment. Its unique anatomical localization and known action spectra support its role in circadian photoreception.