The immune system has developed a number of mechanisms by which to distin guish self from foreign proteins. These mechanisms are found throughout the ontogeny of B and T cell development and include the deletion of autoreactive cells in central lymphoid organs and the induction of self-tolerance in the periphery. However, any failure of these mechanisms for self-tolerance may result in autoimmune disease. Efforts in our laboratory have been directed at under-standing how autoimmunity is initiated and maintained in both the B and T cell compartment, with particular interest in the autoimmunity of systemic lupus erythematosus (SLE). This review will focuson our studies on the forms of self-antigens that may be involved in the original “antigenic sin” of SLE and in the role of B lymphocytes as autoantigen presenting cells. We will also discuss whether costimulation is a formal requirement for the induction and maintenance of autoimmunity. Finally, we have provided a model for how all of these individual elements may contribute to the autoimmune processes leading to pathology.