Autoimmunity results from the failure of self-tolerance of the adaptive immune system. The reactivity of antibodies and T cells against endogenous antigens frequently causes organ damage, and consequent autoimmune disease. Systemic lupus erythematosus (SLE) is an extreme example of such a breakdown of tolerance. Our studies with spontaneous genetic mouse models of SLE and an experimentally induced model have elucidated many of the underlying cellular and genetic mechanisms of this immune dysregulation. We find that the B cell plays a key central role in this process and represents an attractive target for therapeutic intervention.