The clinician must be the ultimate medical detective when dealing with chronic optic neuropathies. History taking is crucial. Clinical examination may require supplementation with visual field testing, fluorescein angiography, ocular and orbital ultrasound imaging, CT and MR imaging, blood test data, and cerebrospinal fluid or tissue biopsy data to determine the specific diagnosis. This supplementation is labor-intensive and time-consuming; the visual loss usually will progress throughout the process, frustrating and frightening the patient and physician. The final common pathway is gradual optic atrophy; the appearance of the optic nerve is rarely adequate to determine the cause of the visual loss. This article includes tables that review diagnostic aids and therapies, and lists the frequency with which several disease entities were encountered over 15 years in one tertiary care neuro-ophthalmic practice. If a specific cause is discernible, then a specific therapy may be available. This approach has the best chance of saving the patient's vision with the least toxicity caused by erroneous trials. By necessity, the work-up for these patients is expensive, but the cost of not pursuing the cause is irrevocable, permanent blindness.