Chronic non-communicable diseases (NCDs) are increasingly recognized as the major cause of morbidity and mortality worldwide. Effective, affordable and broadly accessible medicines for their treatment are much sought after. Therapeutic B-cell vaccines aim at inducing neutralizing auto-reactive antibodies against important mediators of such diseases. Numerous animal models have demonstrated that active immunotherapy can induce disease-modifying levels of auto-antibodies. Recent findings from clinical trials have indicated that self-reactive antibodies can also be readily induced in humans; therapeutic efficacy, however, has not always been achieved. To date, clinical experience with vaccines against self-molecules is limited. Choice of the right target, proper vaccine design, optimal vaccine dose and regimen remain the major challenges to achieve clinical efficacy and safety for this novel class of biotherapeutics.