Neuromyelitis optica (NMO) is a debilitating autoimmune inflammatory disease of the central nervous system (CNS) that is distinct from multiple sclerosis (MS). The discovery of NMO-immunoglobulin G (IgG) in the serum of NMO—but not MS—patients was a breakthrough in defining diagnostic criteria for NMO. NMO-IgG is an antibody directed against the astrocytic water channel protein aquaporin-4 (AQP4). While there is evidence that NMO-IgG is also involved in mediating tissue damage in the CNS, many aspects of the pathogenic cascade in NMO remain to be determined. It is clear that antigen-specific T cells contribute to the generation of NMO-IgG in the peripheral immune compartment, as well as to the development of NMO lesions in the CNS. T helper 17 (Th17) cells, equipped both in providing B cell help and inducing tissue inflammation, may be involved in NMO development and pathogenesis. Here, we review immunologic aspects of NMO, placing recent findings in the biology of T–B cell cooperation into perspective with autoimmunity of the CNS.