Neuromyelitis optica (NMO) is an autoimmune demyelinating disorder for which the aquaporin-4 (AQP4) water channels are the major target antigens. Advances in the understanding of NMO have clarified several points of its pathogenesis, clinical manifestations, and imaging patterns. A major advance was the discovery of the AQP4 antibody, which is highly specific for this disorder. Descriptions of new clinical and radiologic features in seropositive patients have expanded the spectrum of NMO, and the term NMO spectrum disorder (NMOSD) has been adopted. NMOSD is now included in a widening list of differential diagnoses. Acknowledgment of NMOSD imaging patterns and their mimicry of disorders has been crucial in supporting early NMOSD diagnosis, especially for unusual clinical manifestations of this demyelinating disease. This pictorial review summarizes the wide imaging spectrum of NMOSD and its differential diagnosis, as well as its historical evolution, pathophysiology, and clinical manifestations. ©RSNA, 2018.