Myelin oligodendrocyte glycoprotein (MOG) is the only myelin protein known to initiate a demyelinating autoantibody response in EAE, an animal model for multiple sclerosis (MS). The pathophysiological significance of MOG-specific autoantibodies in MS is, however, controversial, as high titer antibody responses to MOG are also found in many patients with non-demyelinating neurological diseases. In this issue of the European Journal of Immunology, von Büdingen et al. demonstrate that demyelination in a primate model of MOG-induced EAE is mediated by MOG-specific antibodies directed against discontinuous, rather than linear, MOG epitopes. This functional segregation of pathogenic vs. non-pathogenic autoantibodies in terms of epitope specificity may be crucial to understand the relevance of MOG-specific responses in human disease. This commentary discusses these findings in the context of the structure and immunobiology of MOG, and their implications with respect to antibody-mediated demyelination in MS.