Mechanisms for visual chromophore production in the retina relevant to cone pigment regeneration. Cone-mediated vision is initiated by photoisomerization of 11-cis-retinaldehyde bound to cone visual pigments, a process that leads to pigment activation and initiation of phototransduction. Photoisomerization leads to the release of all-trans-retinaldehyde from the visual pigment, which must be regenerated to allow for sustained visual function. Two enzymatic systems are thought to contribute to 11-cis-retinaldehyde production for the regeneration of cone pigments. The classical RPE65-dependent visual cycle pathway involves enzymes and retinoid-binding proteins located in photoreceptor outer segments and the RPE. This pathway is also critically involved in rod pigment regeneration. The RPE can store 11-cis-retinoids either in the form of 11-cis-retinaldehyde or 11-cis-retinol complexed with cellular retinaldehyde-binding proteins or, in some species, as 11-cis-retinyl esters. A second cone-specific enzymatic pathway, which is believed to be RPE65 independent and mechanistically distinct from the classical visual cycle, may involve enzymes and binding protein components located in cones and Müller cells. This pathway could generate the 11-cis-retinoids that are present in Müller glia, but such compounds could also originate in the RPE and be transferred through the retina to the Müller cells. Müller cells can store 11-cis-retinoids by the same mechanisms as used by RPE, but the extent of 11-cis-retinyl ester formation is species dependent, typically being higher in diurnal animals. Selective regeneration of cone visual pigments relies on the unique ability of cones to use 11-cis-retinol delivered by Müller cells to form the necessary visual chromophore 11-cis-retinaldehyde. 11-cis-retinaldehyde also can be generated in situ in a light-dependent fashion via photoisomerization of all-trans-retinaldehyde-phosphatidylethanolamine Schiff base adducts. In this figure, solid lines indicate established pathways, whereas dashed lines indicate processes that are either hypothetical or not yet fully characterized. 11cRAL, 11-cis-retinaldehyde; 11cROL, 11-cis-retinol; atRAL, all-trans-retinaldehyde; atRE, all-trans-retinyl ester; atROL, all-trans-retinol; hν, a photon; PE, phosphatidylethanolamine.