Neuromyelitis optica (Devic's syndrome) is an uncommon, idiopathic, demyelinating syndrome of the central nervous system that preferentially affects the optic nerves and spinal cord. It frequently is misdiagnosed as severe multiple sclerosis, but usually is readily distinguished from multiple sclerosis in fully developed cases because of its severity, typical magnetic resonance imaging (MRI) findings (normal brain MRI; longitudinally extensive lesions on spinal cord MRI), and cerebrospinal fluid analysis (polymorphonuclear pleocytosis and absence of oligoclonal banding). A serum autoantibody marker, NMO-IgG, is highly specific for the disorder. Most patients have relapsing disease, and natural history studies confirm early and severe disability. We treat acute myelitis and optic neuritis exacerbations with parenteral corticosteroids and use rescue plasmapheresis for severe, refractory attacks. Immunomodulatory drugs used for typical multiple sclerosis seem ineffective for relapse prevention. We recommend systemic immunosuppression, usually with azathioprine and oral corticosteroids, for most patients. Fulminant disease and breakthrough disease may respond to other forms of humoral immunotherapy such as rituximab.