^ Leber's hereditary optic neuropathy (LHON) is a bilateral subacute optic neuropathy caused by mutations in the mitochondrial genome. Primary mutations are located at nucleotide positions 3460, 11778, and 14484 in genes encoding subunits of Complex I of the respiratory chain. Molecular diagnosis has expanded the spectrum of the LHON phenotype and prompted investigation into optic neuropathies due to demyelinating disease, glaucoma, tobacco/alcohol amblyopia, and nutritional optic neuropathy. While mitochondrial mutations are for LHON disease expression, other genetic or epigenetic factors must play a role in disease penetrance and expression. Prodeterminants of disease include heteroplasmy, an X-linked vision susceptibility locus, environmental factors, and secondary mitochondrial mutations.