While evidence of dysregulation of the B cell compartment was first demonstrated with the identification of autoantibodies, other functional roles of B lymphocytes in autoimmune pathogenesis have generally been underappreciated or completely overlooked. With the recent approval of the first B cell targeting agent in rheumatoid arthritis, new strategies are being developed to target B cells through a range of membrane-associated lineage-specific molecules and also by interfering with B-cell-specific pro-survival signals. B-cell-directed agents therefore provide an effective new mechanistic approach to treatment and also enable new perspectives from the dissection of the contributions of B cells in physiologic and pathologic immune responses.