Increasing evidence has suggested that both antibody-dependent and antibody-independent functions of B cells are involved in multiple sclerosis (MS). The contrasting results of distinct B-cell targeting therapies in MS patients underscores the importance of elucidating these multiple B-cell functions. In this review, we discuss the generation of autoreactive B cells, migration of B cells into the central nervous system (CNS), and how different functions of B cells may contribute to MS disease activity and potentially mitigation in both the periphery and CNS compartments. In addition, we propose several future therapeutic strategies that may better target/shape B-cell responses for long-term treatment of MS.