Retinal stem cells (RSCs) are multipotent central nervous system (CNS) precursors that give rise to the retina during the course of development. RSCs are present in the embryonic eyecup of all vertebrate species and remain active in lower vertebrates throughout life. Mammals, however, exhibit little RSC activity in adulthood and thus little capacity for retinal growth or regeneration. Because CNS precursors can now be isolated from immature and mature mammals and expanded ex vivo, it is possible to study these cells in culture as well as following transplantation to the diseased retina. Such experiments have revealed a wealth of unanticipated findings, both in terms of the instructive cues present in the mature mammalian retina as well as the ability of grafted CNS precursors to respond to them. This review examines current knowledge regarding RSCs, together with other CNS precursors, from the perspective of investigators who wish to isolate, propagate, genetically modify, and transplant these cells as a regenerative strategy with application to retinal disease.