The immunologic basis of systemic autoimmune diseases such as systemic lupus erythematosus (SLE) is complex and multifaceted. Recent advances in the field of apoptosis have suggested new paradigms for the development of autoimmunity. This review examines the role that apoptosis plays in maintaining immunologic tolerance to self-antigens, and how abnormalities in the regulation of apoptosis can lead to a breakdown in self-tolerance. This article also examines the increasing recognition of apoptotic cell antigens as the targets of autoantibodies and discusses the possibility that the autoimmune response characteristic of SLE is specifically directed against apoptotic cells. In addition, we will describe some of the features that distinguish nonpathogenic anti-DNA autoantibodies from those which deposit in the kidney and lead to lupus nephritis. Finally, we will attempt to synthesize the vast body of data connecting apoptosis and SLE into a single hypothesis in which we suggest that apoptotic cells are a primary source of immunogen, and that abnormalities in the handling of apoptotic cells can lead to a breakdown in self-tolerance.