Systemic lupus erythematosus is a complex, multisystem autoimmune disease characterized by production of high-titer autoantibodies directed against ubiquitously expressed self-antigens. Autoantigens in systemic lupus erythematosus are highly diverse in terms of structure and location in control cells, but become clustered in and on the surface blebs of apoptotic cells. The past several years have provided significant evidence that the apoptotic cell plays a central role in tolerizing B cells and T cells to both tissue-specific and ubiquitously expressed self-antigens, and may drive the autoimmune response in systemic autoimmune disease. The authors review the significant recent advances in this area. Recent studies suggest that predisposing factors to subsequent development of systemic autoimmunity may be the incomplete induction of tolerance to apoptotic antigens, potentially through abnormal apoptotic signaling and effector pathways, decreased apoptotic cell clearance, or abnormal signaling thresholds on responding lymphocytes. In such genetically susceptible hosts, proinflammatory events at the host-environment-immune system interface that lead to the binary change in the response to apoptotic material from tolerance to immunity may be responsible for initiation of autoimmunity and subsequent disease amplification. Such pathways may be amenable to therapeutic and preventive interventions.