New insights into the mechanisms of autoimmune diseases have been obtained not only from preclinical studies, but also from clinical trials of pan-B-cell-directed therapy. Overall, the results of these clinical trials suggest that more-specific approaches focusing on pathogenic B-cell functions, and perhaps sparing or even enhancing regulatory B-cell activity, might be attractive alternatives. Importantly, pathogenic B-cell subpopulations function within a network of cellular interactions, many of which might require additional interventions to restore immunologic balance and suppress autoimmune disease. Thus, approaches that simultaneously target innate immune cells as well as multiple nodes of T-cell and B-cell interactions might hold the promise of improved therapeutic efficacy. Interfering with B-cell intracellular signalling pathways, altering their intracellular metabolic pathways and perturbing transcription factors are additional options. This Review critically analyses these approaches, examines the role of cytokines and other functions of B-lineage cells separate from antibody secretion, and provides insights into the potential next generation of therapies targeting B-lineage cells.