A prime goal of regenerative medicine is to direct cell fates in a therapeutically useful manner. Retinitis pigmentosa is one of the most common degenerative diseases of the eye and is associated with early rod photoreceptor death followed by secondary cone degeneration. We hypothesized that converting adult rods into cones, via knockdown of the rod photoreceptor determinant Nrl, could make the cells resistant to the effects of mutations in rod-specific genes, thereby preventing secondary cone loss. To test this idea, we engineered a tamoxifen-inducible allele of Nrl to acutely inactivate the gene in adult rods. This manipulation converted the rods into cone-like cells, thereby preventing retinal degeneration in a mouse model of blindness. This rescue is the first therapeutic effect that has ever been achieved via direct cellular reprogramming in the mammalian central nervous system. Current efforts are directed toward achieving complete reprogramming of rods into cones. If successful, reprogrammed rods could serve as a localized, in situ source of novel cones in diseases that preferentially afflict this cell type, such as age-related macular degeneration.