The determination of disease-specific autoantibodies (Abs) is a challenge in any autoimmune disease. The significance of Abs detected in inflammatory demyelinating diseases (IDD) of the central nervous system (CNS), such as multiple sclerosis (MS), is still unclear. Histopathological reports have demonstrated that a humoral (Abs)-mediated pattern of demyelination is detected in >50% of MS patients and is consistently associated with active demyelination. The observation that these patients specifically respond to plasmapheresis reinforces the hypothesis of a specific humoral MS subtype. One of the most intensively studied antigen targets in MS is a glycoprotein of the myelin sheath called the Myelin Oligodendrocyte Glycoprotein (MOG). Recent advances have shown that epitope specificity of MOG is crucial in terms of specificity of the Ab response. Several other auto-Abs, including anti-myelin, oligodendrocyte and neuronal Abs have been studied in MS. These auto-Abs may have pathogenic or protective properties, but could also have no functional role. Recently, the demonstration of a highly specific auto-Ab in an IDD of the CNS called neuromyelitis optica (NMO), directed against the aquaporin-4 (AQP-4) located at the blood brain barrier (BBB), has allowed a refinement of the diagnostic criteria of NMO and classification of this disease as an autoimmune channelopathy. These recent advances have reinforced the interest in tracking the role of the humoral response in the different IDD of the CNS.