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Experimental models of human diseases have affected the design and direction of both basic and clinical research into understanding the pathogenesis and treatments of demyelinating disease, stroke, and hereditary disorders of the central nervous system. However, in spite of major advances in molecular research that have linked Leber Hereditary Optic Neuropathy to mutations in mitochondrial DNA, there has been relatively little focus in applying basic scientific methodologies to optic neuropathies other than glaucoma. The relative absence of detailed scientific knowledge about the basic mechanisms involved in the pathogenesis of optic nerve injury has contributed to the use of empiric therapies for neuro-ophthalmic optic neuropathies. Over the past decade major clinical trials, such as the Optic Neuritis Treatment Trial and Ischemic Optic Neuropathy Decompression Trial, have proven that currently available treatment options for demyelinating and ischemic optic neuropathies are ineffective and can even be harmful. Although the pathogenesis of visual failure in demyelinating, ischemic, and hereditary optic neuropathies appears diverse, a final common pathway for irreparable optic nerve injury may exist. This article reviews several models of experimental optic neuropathies that may aid in the development of novel treatments for neuro-ophthalmic disorders of the optic nerve during the 21st century.