NMO-IgG, the auto-antibody specific to the aquaporin-4 (AQP4) water channel associated with the autoimmune inflammatory disease neuromyelitis optica (NMO), is considered to be an accurate serum biomarker and is thought to be an important contributor to NMO pathology. In this review, we summarize recent evidences from our group and others indicating that NMO-IgG can be implicated at several levels in the immuno-pathology of NMO. NMO-IgG/anti-AQP4 antibodies may compromise the integrity of the blood-brain barrier and consequently facilitate and enhance the perivascular inflammation characteristic of NMO. Lastly, NMO-IgG can induce astrocyte injury which may lead to the accumulation of excitatory/toxic molecules and accordingly damage oligodendrocytes and compromise myelin integrity.