The mechanisms that mediate the degeneration of retinal ganglion cells (RGCs) during glaucoma development are unknown. Williams et al. report that decreased levels of NAD+ and mitochondrial dysfunction are among the very first changes to occur in retinas of a mouse model of glaucoma. Orally administered vitamin B3 (also known as nicotinamide, which is a precursor of NAD+) and/or intravitreal injection of an adenovirus overexpressing NMNAT1 (a key NAD+-producing enzyme) protected mice from glaucomatous RGC degeneration when given prophylactically or therapeutically.