Neuromyelitis optica (NMO) and a related spectrum of inflammatory CNS disorders are unified by detection of a serum autoantibody specific for the aquaporin-4 (AQP4) water channel, which is abundant in astrocytic foot processes. The classic clinical manifestations of NMO are optic neuritis and longitudinally extensive transverse myelitis. Newly recognized manifestations of AQP4 autoimmunity include lesions of circumventricular organs and skeletal muscle. NMO is commonly relapsing, is frequently accompanied by other autoimmune disorders, and sometimes occurs in a paraneoplastic context. The goals of treatment are to minimize neurologic disability in the acute attack and thereafter to prevent relapses and cumulative disability. The disease specificity of AQP4 immunoglobulin (Ig) G approaches 100% using optimized molecular-based detection assays. Clinical, immunohistopathologic, and in vitro evidence support this antibody being central to NMO pathogenesis. Current animal models yield limited histopathologic characteristics of NMO, with no clinical deficits to date. Recent descriptions of a myelin oligodendrocyte glycoprotein autoantibody in a minority of patients with NMO spectrum phenotype who lack AQP4-IgG predict serologic delineation of additional distinctive disease entities.