Abstract: Recent studies have revealed that B cells serve extraordinarily diverse functions within the immune system in addition to antibody production. These functions contribute to autoimmunity. They initiate the development of lymphoid architecture and regulate dendritic and T-cell function through cytokine production. Receptor editing is also essential to prevent autoimmunity. Both abnormalities in the distribution of B-cell subsets and the benefits of ablative B-cell therapy of autoimmune states confirm their importance. Results from transgenic models have demonstrated that the sensitivity of B cells to antigen receptor cross-linking correlates to autoimmunity, with particular reference to negative signaling by CD5 and CD22. These mechanisms maintain tolerance by recruiting src-homology 2 domain-containing protein tyrosine phosphatase-1. These findings open new prospects for immunotherapy of autoimmune diseases.