Self-reactive B lymphocytes play two main pathological roles in autoimmune diseases: as secretors of autoantibodies and as specialized antigen-presenting cells that present self-components to autoreactive T lymphocytes. In recognition of these roles, recent clinical trials have utilized B-lymphocyte-depleting monoclonal antibodies to treat various autoimmune diseases, with encouraging results in those where humoral autoimmunity is clearly important. Surprisingly, recent results in animal models suggest that B-lymphocyte depletion may also be effective in the treatment of T-lymphocyte-mediated autoimmune diseases, such as Type 1 diabetes (T1D). This article reviews the experimental evidence that has uncovered pathogenic as well as regulatory roles for B lymphocytes in the prodrome of T1D and how this information is being used to develop novel therapeutic strategies to treat the disease.