NMO-IgG autoantibody is now considered a useful serum biomarker of neuromyelitis optica (NMO). A series of clinical and pathological observations suggest that NMO-IgG may play a central role in NMO physiopathology. Although the exact role and function of NMO-IgG in vivo remain to be determined, recent reports suggest that this antibody that targets the aquaporin-4 (AQP-4) water channel expressed by astrocytes is able to destabilize the blood-brain barrier and contribute to astrocyte and oligodendrocyte damage. This review summarizes the latest molecular effector functions attributed to the NMO-IgG/anti-AQP4 antibody and discusses their potential role in NMO pathology.