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B lymphocytes contribute to immunity through organogenesis of secondary lymphoid organs, presentation of antigen to T cells, production of antibodies, and secretion of cytokines. Their roles in autoimmune diseases are complex. Clinical trials have shown that depleting B cells can significantly ameliorate such diseases, underlining the contributions of B cells to pathogenesis. Conversely, B-cell depletion can lead to exacerbation of symptoms in some patients. In mice, B cells can offer protection from chronic autoimmune pathologies. It is important to understand the mechanisms responsible for the distinct roles of B cells in autoimmune diseases, and investigation of these processes could highlight new therapeutic strategies. Here, we review recent progress in our understanding of the suppressive functions of activated B cells in mice, as well as the promising potential of B cells for use as cell-based therapy for experimental autoimmune diseases, and, finally, discuss the possibility of translating this cellular approach to treat human autoimmune diseases.