B-cell-targeted therapy for autoimmune disease emerged from theoretical proposition to practical reality between 1997 and 1998, with the availability of the B-cell-depleting monoclonal antibody rituximab. Since then, a score of autoantibody-associated disorders have been treated, with most convincing evidence of efficacy seen in subjects with rheumatoid arthritis. Several classes of B-cell-targeted agent are now under investigation. From the outset, a major goal of B-cell targeting has been the re-establishment of some form of immunological tolerance. In some subjects, the observed improvement of disease for years following therapy fuels hope that this goal might ultimately be achievable.