The pathogenic roles of B cells in human autoimmune diseases involve a multitude of mechanistic pathways and include the well-established contributions of autoantibodies and immune complexes that induce local inflammatory reactions and tissue destruction. Recent results using several novel B cell-directed therapies have provided new insights into additional roles of B cells in human autoimmunity. In this review, we will highlight some of these studies and discuss how clinical insights parallel murine models of normal immunity and autoimmunity.