Multiple sclerosis is a common neurological disorder that represents a significant source of disability. B cells have recently emerged as a novel therapeutic target for multiple sclerosis. The natural development of B cells is characterized by an antigen-independent phase that occurs in the bone marrow and an antigen-dependent phase that takes place in the peripheral lymphoid tissue. The stage of B-cell development can be identified by the presence of specific cell surface markers. Checkpoints are in place to prevent self-reactive B cells from further development and activation. Some self-reactive B cells are able to escape these checkpoints, resulting in a loss of tolerance. B cells may contribute to systemic autoimmunity and the development of autoimmune disease via cytokine production, antigen presentation, and complement activation. In addition, B cells may trigger autoimmune disease via molecular mimicry, which occurs when a single B-cell receptor recognizes both a non-self antigen molecule and a self-molecule. Accumulating data suggest that ectopic proliferation of B cells in the central nervous system may also play a role. Further research is needed to elucidate the pathology of B cells and their role in central nervous system autoimmune diseases, including multiple sclerosis.