Recent advances in the field of neuromyelitis optica (NMO) research provided convincing evidence that anti-AQP4 antibody (AQP4-Ab) not only serves as a highly specific disease marker, but also plays an essential role in the pathogenesis of the disease. Although it is now widely recognized that AQP4-Ab induces astrocytic necrosis in a complement-dependent manner, additional triggers are also suspected as a prerequisite for the development of the disease. Unraveling these unresolved aspects of the disease will provide substantial insight into still controversial issues in the pathogenesis of NMO.