The discovery of serum autoantibodies against the astrocytic water channel aquaporin-4 (AQP4) as a biomarker of neuromyelitis optica (NMO, Devic syndrome) has revolutionized our understanding of this rare immune-mediated clinical entity and has provided a rationale for the use of therapeutic strategies targeting the humoral effector arm of autoimmune responses. This article reviews the clinical features of NMO and highlights recent findings that have elucidated how antibodies and T cells with specificity for AQP4 may be involved in the pathophysiology of the disorder.