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 nondemyelinating 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.