The understanding of neuromyelitis optica spectrum disorder (NMOSD) has evolved substantially since its initial description over a century ago. The discovery in 2004 of a pathogenic autoantibody biomarker targeting aquaporin 4 IgG revolutionized diagnosis and therapeutic development. Although NMOSD resembles multiple sclerosis (MS), differences were identified and articulated in the late 1990s. New diagnostic criteria incorporating the biomarker as well as better understanding of the clinical and radiologic features of NMOSD now permit accurate diagnosis and differentiation from MS. Aquaporin 4 IgG–associated NMOSD is now regarded as an immune astrocytopathy with lytic and nonlytic effects on astrocytes. A second autoantibody, myelin oligodendrocyte glycoprotein IgG, which targets myelin rather than astrocytes, leads to an NMOSD syndrome with clinical and radiologic features that overlap but are distinct from those of aquaporin 4 IgG–associated NMOSD and MS. We review current understanding of the clinical aspects, pathophysiology, and treatment of NMOSD.