Extracellular signaling molecules have been implicated in the progression of Retinal Degeneration (RD). Gene regulatory events linked to the maintenance of retinal structure and function incorporate signaling cascades that may serve as therapeutic targets for some forms of blindness. This review shall focus on the evidence for non-cell-autonomous mechanisms that affect the pattern of degeneration seen in retinal dystrophies, the types of signals that may influence the course of degeneration and finally with the related prospects for retinal-therapies.