SLE is a heterogeneous and complex group of disorders of uncertain cause. Recent studies have suggested that abnormalities in the apoptotic cell death process may play an important role in the initiation and propagation of this spectrum of disease by altering the generation and cleavage of antigens, and through abnormalities in immunoregulation. The clustering and concentration of autoantigens in and on the surface blebs of apoptotic cells, modifications of antigen structure during certain forms of apoptotic death, and abnormalities in apoptotic cell clearance in humans with SLE and in certain animal models are reviewed and synthesized into a comprehensive model of systemic autoimmunity.