Vision loss in glaucoma is associated with death of retinal ganglion cells. High intraocular pressure is a major risk factor for vision loss from glaucoma, and lowering eye pressure is the goal of all available medical and surgical treatments. Taking a bold step forward, the restoration of vision after severe glaucoma damage is a new Audacious Goal established by National Eye Institute (Sieving, 2012). This means that retinal ganglion cell repair, and replacement, must be considered in the context of visual function restoration. To restore visual function, retinal ganglion cells, after long-distance axonal growth and guidance, should connect to specific target neurons in subcortical visual structures. At the time of the establishment of these connections, the fate of target cells is critical along with the health of retinal ganglion cells. In fact, several lines of evidence demonstrate glaucomatous neural degeneration occurs throughout the central visual system where most information processing takes place. Evidence from multiple studies in experimental glaucoma models, human autopsy cases and neuroimaging studies point to the degeneration of neurons in the lateral geniculate nucleus, a subcortical hub of functional connectivity between the eye and the visual cortex. Maintaining and re-establishing connections of retinal ganglion cells to target neurons in major visual structures is a key endpoint for regenerative medicine strategies. This paper critically reviews studies of visual brain changes in man and experimental animal models, and discusses key factors in the experimental design that are relevant to restoring vision loss in human disease.