Increasing research activities on humoral immune responses involved in the immunopathogenesis of multiple sclerosis (MS) led to a revival of the importance of B cells and antibodies in MS. B cells seem now to play various immunopathogenetic roles in the initiation and propagation of inflammatory demyelinating processes at different disease stages of MS. The biological activities of antibodies in MS is, in general, still less known, although it emerges that antibodies are specifically involved in demyelination or, at least, mirror tissue destruction in the central nervous system. Finally, there is growing evidence that treatments, which specifically target B cells and/or antibodies, are effective in MS and its variants neuromyelitis optica (NMO). This chapter therefore aims to summarize the present knowledge and to outline future directions about the role of B cells and antibodies in research and therapy of MS and NMO.