Abstract Currently, there are no effective therapies to replace degenerated neurons in patients with retina neuron loss from degenerative diseases, such as occurs in patients with glaucoma and macular degeneration. By contrast, retinas of non-mammalian vertebrates, such as fish and amphibians, show a robust regenerative response following retinal damage. Upon injury to the retina, fish Muller Glia generate all different types of retinal neurons to replace those that were lost. There has been considerable progress in understanding the molecular mechanisms of regeneration in non-mammalian vertebrates, and if this knowledge could be applied to humans, it might lead to the development of new types of regenerative therapies for patients with impaired vision. Five years ago, we discovered that by expressing a key proneural regulatory gene, called Ascl1, in the Muller glia of mice, we can induce them to regenerate new neurons after injury. The new regenerated neurons in the mouse retinas wired up with the existing, undamaged neurons and became functional. These results showed for the first time that functional neuron regeneration is possible in mammals, like ourselves; however, we have found that additional factors are likely required to guide the regeneration to the proper types and numbers of neurons needed to address specific diseases. In this proposal, our aim is to better define the specific transcription factor combinations that best regenerate each of the major retinal neurons types. We also propose to determine whether the types of neurons regenerated by the Muller glia are influenced by the type of retinal injury, and whether the process can be made efficient enough to restore functional vision in animal models of retinal degeneration. Lastly, we propose studies to better understand the signaling pathways that could be harnessed to further direct the MG-mediated regeneration process. At the end of five years, we expect to have further refined the potential for regeneration in the treatment of retinal disease and trauma.