B cells play a central role in multiple sclerosis (MS) pathology. B and plasma cells, and their antibody products, are found at elevated levels in MS patient cerebrospinal fluid and demyelinating lesions, and B cell-predominant germinal center-like aggregates are observed in relapsing and secondary progressive patients MS patients. In Phase 3 clinical trials, relapsing MS patients treated with anti-CD20 monoclonal antibodies demonstrate reduced MRI lesion activity, clinical relapses, and disability progression; and early Phase 2 clinical studies of Bruton’s tyrosine kinase inhibitors show reduction in active MRI lesions. B and plasma cells may modulate MS disease activity through multiple mechanisms including antigen presentation, pro- and anti-inflammatory cytokine secretion, and auto-antibody production. Molecular and functional analyses of B cell populations have indicated that B cell subpopulations and mature antibody producing cells (plasmablasts and plasma cells) display complex interactions with other immune cell populations to modulate MS disease activity in the periphery and within the central nervous system. These effects are further modified by secreted immunoglobulins acting independently or in concert with other cellular immune responses. Sophisticated translational investigations and experimental models are primed to expand our understanding of MS B cell pathophysiology and advance the development of new B cell therapeutics.