Abstract: Various clinical and experimental findings suggest a pathogenic role of antibodies in multiple sclerosis (MS). Yet, whether antibodies contribute to the pathogenesis or progression of MS is still a subject of intense debate. This controversy particularly results from unclarity regarding the target antigens of the antibodies that are found in the central nervous system (CNS) of MS patients. The identification of such target antigen(s) at disease onset remains an important topic of investigation, but these antigens may be heterogeneous and not the decisive factor for the initiation of MS development. In addition to antigen-specific binding of IgG, IgG may also promote pathology in MS patients by binding in an antigen non-specific manner. Therefore, we propose that we should not only focus on the antigen-binding part of MS antibodies, but also should pay attention to the other side of the antibodies in the CNS of MS patients, i.e. the fragment crystallizable (Fc) tail (Figure 1A). The characteristics of the Fc tail, particularly the (combination of) IgG subclass, allotype, and glycosylation determine the pathogenicity of IgG, but these characteristics are still poorly defined in MS. Unraveling these characteristics may not only lead to better understanding of MS pathogenesis, but may also yield new strategies for therapy.