The predominant manifestation of Leber hereditary optic neuropathy (LHON) is a sudden and usually severe bilateral loss of central vision, most often in the mid-20s, that is due to a degeneration of the ganglion cell layer and optic nerve. LHON is an inherited form of blindness in which a mutation in the mitochondrial genome (mtDNA) is the primary etiological event. More than 95% of the LHON pedigrees in peoples of Northern European descent harbor one of the three mitochondrial mutations at nucleotides 3460, 11,778 and 14,484, although there are other rare primary mutations. In addition, there may be mtDNA mutations that have a secondary etiological role. The penetrance of the optic neuropathy is incomplete in LHON families, and males are affected much more often then females. The incomplete penetrance indicates that secondary etiological factors are necessary for the development of the optic neuropathy, although they are poorly understood at the present time. Several types of studies suggest that optic nerve function in LHON patients is impaired in the presymptomatic phase, probably as a result of a mitochondrial respiratory chain abnormality, although visual acuity is not compromised. In some family members, the presence of secondary etiological factors triggers a wave of optic nerve dysfunction in which vision is lost (the acute phase). Depending upon the particular primary LHON mutation that the patient carries, a variable proportion of the dysfunctional ganglion cells and optic nerve axons die during the atrophic phase, probably through an apoptotic pathway. In 11,778 LHON patients, retinal ganglion cell degeneration occurs almost without exception, and recovery of vision is extremely rare. In contrast, activation of the cell death pathway is less frequent, or less extensive, in 14,484 LHON patients and there is often a substantial recovery of vision.