Almost all optic neuropathies are untreatable, motivating the search for new therapies that address the final common pathway of optic nerve disease, retinal ganglion cell loss. These neuroprotective strategies have been primarily studied in glaucoma, the most common optic neuropathy, but increasing also tested at the laboratory and animal model level in nonglaucomatous optic neuropathies. More recently, several clinical trials, most of which are randomized, have begun to examine whether neuroprotection is efficacious in human optic nerve disease. Many of these trials are reviewed, along with the critical issues in the major areas of optic neuropathy, particularly the site of injury, the mechanism of axonal damage, and disease-specific features relevant to neuroprotection studies.