Regeneration of the chromophore 11-cis-retinal is essential for the generation of light-sensitive visual pigments in the vertebrate retina. A deficiency in 11-cis-retinal production leads to congenital blindness in humans; however, a buildup of the photoisomerized chromophore can also be detrimental. Such is the case when the photoisomerized all-trans-retinal is produced but cannot be efficiently cleared from the internal membrane of the outer segment discs. Sustained increase of alltrans-retinal can lead to the formation of toxic condensation products in the eye. Thus, there is a need for potent, selective inhibitors that can regulate the flux of retinoids through the metabolism pathway termed the visual (retinoid) cycle. Here we systematically study the effects of the most potent inhibitor of this cycle, retinylamine (Ret-NH 2 ), on visual function in mice. Prolonged, sustainable, but reversible suppression of the visual function was observed by Ret-NH 2 as a result of its storage in a prodrug form, N-retinylamides. Direct comparison of other inhibitors such as fenretinide and 13-cis-retinoic acid showed multiple advantages of Ret-NH 2 and its amides, including a higher potency, specificity, and lower transcription activation. Our results also revealed that mice treated with Ret-NH 2 were completely resistant to the light-induced retina damage. As an experimental tool, Ret-NH 2 allows the replacement of the native chromophore with synthetic analogs in wild-type mice to better understand the function of the chromophore in the activation of rhodopsin and its metabolism through the retinoid cycle.In the photoreceptors of the vertebrate retina, light causes the isomerization of the visual pigments' chromophore, 11-cis-retinylidene, to all-trans-retinylidene, followed by the release of all-trans-retinal from the opsin binding pocket and its reduction to all-trans-retinol (McBee et al., 2001;Lamb and Pugh, 2004;Palczewski, 2006). Vitamin A (all-transretinol) diffuses to the retinal pigment epithelium (RPE), where it is esterified by lecithin/retinol acyltransferase (LRAT) to all-trans-retinyl esters and stored in the retinosomes (Imanishi et al., 2004a,b). All-trans-retinyl esters are isomerized to 11-cis-retinol in a reaction that involves an abundant 65-kDa RPE-specific protein, termed RPE65, proposed to be retinoid isomerase (Jin et al., 2005;Moiseyev et al., 2005;Redmond et al., 2005). To complete the cycle, 11-cis-retinol is then oxidized to its aldehyde. 11-cis-Retinal diffuses across the extracellular space to photoreceptors and recombines with opsins to regenerate visual pigments (McBee et al., 2001;Lamb and Pugh, 2004).The accumulation of fluorescent materials, lipofuscin, in the RPE is associated with aging. In humans, one of the major fluorescent compounds found most prominently in the macula is a pyridinium bis-retinoid, which is derived from two molecules of all-trans-retinal and one molecule of phosphatidylethanolamine, called N-retinylidene-N-retinyl ethanolamine (A2E) (Parish et al., 1998), w...