In addition to rods and cones, mammals have inner retinal photoreceptors called intrinsically photosensitive retinal ganglion cells (ipRGCs), which use the photopigment melanopsin and mediate nonimage-forming visual responses, such as pupil reflexes and circadian entrainment. After photic activation, photopigments must be reverted to their dark state to be light-sensitive again. For rods and to some extent cones, photopigment regeneration depends on the retinoid cycle in the adjacent retinal pigment epithelium (RPE). By contrast, ipRGCs are far from the RPE, and previous work suggests that melanopsin is capable of light-dependent self-regeneration. Here, we usedin vitroipRGC recording andin vivopupillometry to show that the RPE is required for normal melanopsin-based responses to prolonged light, especially at high stimulus intensities. Melanopsin-based photoresponses of rat ipRGCs were remarkably sustained when a functional RPE was attached to the retina, but became far more transient if the RPE was removed, or if the retinoid cycle was inhibited, or when Müller glia were poisoned. Similarly, retinoid cycle inhibition markedly reduced the steady-state amplitude of melanopsin-driven pupil reflexes in both mice and rats. However, melanopsin photoresponses in RPE-separated rat retinas became more sustained in the presence of an11-cis-retinal analog. In conclusion, during prolonged illumination, melanopsin regeneration depends partly on11-cis-retinal from the RPE, possibly imported via Müller cells. Implications for RPE-related eye diseases and the acne drug isotretinoin (a retinoid cycle inhibitor) are discussed.