Neuromyelitis optica (NMO) was historically defined by the concurrent or sequential presentation of optic neuritis and transverse myelitis. Serum autoantibodies against aquaporin-4 (AQP4-IgG) and myelin oligodendrocyte glycoprotein (MOG-IgG) have been identified in patients meeting clinical criteria for NMO and neuromyelitis optica spectrum disorders (NMOSD). Despite their clinical overlap, these two autoantibody-defined inflammatory disorders present with diverse neurologic findings across the pediatric and adult populations, distinct lesion histopathology, and disparate pathophysiology in experimental animal models. Therefore, it is important to be able to rapidly distinguish these conditions based on clinical, radiologic, and laboratory data due to differences in both their prognosis as well as their acute and chronic treatments. This lecture will focus on distinguishing these disorders based on their clinical phenotypes, MRI imaging, serologic assays, mechanisms of antibody-mediated pathogenesis, and histopathology.