A subset of melanopsin-expressing retinal ganglion cells has been identified to be directly photosensitive (pRGCs), modulating a range of behavioral and physiological responses to light. Recent expression studies of melanopsin have provided compelling evidence that melanopsin is the photopigment of the pRGCs. However, the mechanism by which melanopsin transduces light information remains an open question. This review discusses the signaling pathways that may underlie melanopsin-dependent phototransduction in native pRGCs, as well as the many exciting challenges ahead.