Neuromyelitis optica (NMO) is an idiopathic CNS demyelinating disorder that preferentially involves the optic nerve and spinal cord. Diverse sources of evidence support the hypothesis that NMO is distinct from classical multiple sclerosis (MS) and that the pathogenesis of NMO is dominated by humoral mechanisms. Such evidence includes clinical observations that systemic autoimmune diseases often coexist with NMO and that therapeutic plasmapheresis may provide meaningful rescue therapy for severe clinical attacks, immunopathologic studies that demonstrate prominent complement activation and immunoglobulin deposition, and the discovery of the serum autoantibody NMO-IgG, a potential NMO biomarker that targets aquaporin-4 (AQP4). The NMO-IgG marker is present in a majority of patients with "NMO-spectrum disorders," including isolated or recurrent longitudinally extensive transverse myelitis, recurrent optic neuritis with negative brain imaging, and the Asian optic-spinal form of MS. Preliminary experiments demonstrate that NMO-IgG can modulate AQP4 function and fix complement, characteristics that suggest it has the potential to be pathogenic in NMO. Other immunologic differences among NMO, NMO-spectrum disorders, and classical MS are reviewed.