Melanopsin-expressing ganglion cells have been proposed as the photoreceptors mediating non-rod, non-cone ocular responses to light. Here we use the aged (approximately 2 years) rodless and coneless (rd/rd cl) mouse to assess the impact of progressive inner retinal cell loss on melanopsin expression, circadian entrainment and pupillary constriction. Aged rd/rd cl mice show substantial transneuronal retinal degeneration leaving only the ganglion cell layer and little of the inner nuclear layer. Despite this loss, quantitative reverse transcriptase-polymerase chain reaction showed normal levels of melanopsin expression, and immunocytochemistry demonstrated both the presence and normal cellular appearance of these cells. Furthermore, the optic nerves of the two genotypes (rd/rd cl and +/+) were not obviously different in animals older than 2 years. However, this massive level of retinal degeneration left both pupillary and circadian responses to light intact, even in rd/rd cl mice older than 2 years. Our data provide the first positive correlation between the persistence of melanopsin-expressing cells and the maintenance of both circadian and pupillary responses to light in the absence of rods and cones. These findings, together with recent studies on melanopsin knockout mice, are consistent with the hypothesis that melanopsin-expressing ganglion cells are photosensitive and mediate a range of irradiance-detection tasks.