The failure of the optic nerve to regenerate after injury or in neurodegenerative disease remains a major clinical and scientific problem. Retinal ganglion cell (RGC) axons course through the optic nerve and carry all the visual information to the brain, but after injury, they fail to regrow through the optic nerve and RGC cell bodies typically die, leading to permanent loss of vision. There are at least 4 hurdles to overcome in preserving RGCs and regenerating their axons: 1) increase RGC survival, 2) overcome the inhibitory environment of the optic nerve, 3) enhance RGC intrinsic axon growth potential, and 4) optimize the mapping of RGC connections back into their targets in the brain.