Neuromyelitis optica (NMO) is an antibody-mediated inflammatory disease of the central nervous system with a predilection for the optic nerves, spinal cord, and certain brain regions. While NMO was previously considered a variant of multiple sclerosis (MS), it is now known to have distinct clinical, pathological, and immunological features. The identification of AQP4-IgG, a pathogenic antibody against aquaporin-4 (AQP4), delineated NMO from MS and markedly advanced insights into the unique features of this disease. The specificity of this antibody has allowed an expanded view of the clinical presentations of NMO-spectrum disorders (NMOSD), without requiring all the clinical features that were previously essential to make a clinical diagnosis. Early, accurate diagnosis of patients with NMOSD permits treatment with appropriate acute and long-term immunosuppressive agents that are critical to mitigate the risk of disability associated with this disease. More recently, a subset of patients with the NMOSD phenotype have been found to have autoantibodies targeting myelin oligodendrocyte glycoprotein (MOG), which has a different pathogenesis and expected outcome. Better understanding of the distinct pathophysiology of these disorders has laid the foundation for targeted efforts to develop novel, disease-specific treatments. In this review, we discuss the revised diagnostic criteria for NMOSD, appraise the diagnostic significance of the AQP4-IgG and MOG-IgG tests, review evidence supporting the use of available treatments for acute episodes and long-term disease modification, and highlight key emerging immunotherapies.