Systemic lupus erythematosus is a multisystemic autoimmune disease. The immunopathogenesis is characterized by the loss of tolerance to self. While many abnormalities in the immune system have been detected, genetic factors play a central role in the pathogenesis. The event proximate to target organ involvement appears to be autoantigen-driven, T cell-mediated, B cell activation. High levels of autoantibodies are produced. However, not all autoantibodies are pathogenic to the kidney (i.e. 'nephritogenic'). These nephritogenic autoantibodies appear to share specific physiochemical features that correlate well with patterns of renal injury. While DNA was initially regarded as the inciting autoantigen, this view does not appear to be supported by the prevailing evidence. Nucleosomes, which are structures comprising histones and DNA, have emerged as the more likely candidate autoantigen. Autoantibodies directed against nucleosomes that cross-react with nucleosomal epitopes have been identified. Furthermore, evidence suggests that immunoglobulin-nucleosomal complexes may be important in target organ immune deposition. In-vivo generation of nucleosomes requires apoptosis; in fact, there are several examples of aberrant apoptotic processes that present with autoimmunity. Aberrant apoptosis may also be critical in lupus immunopathogenesis. Indeed, studies on Fas/FasL and Bcl-2 in animal models and in humans have underscored the importance of apoptosis as an etiological factor in lupus. Cytokines, hormonal, infectious and environmental factors have also been found to be important in the pathogenesis of systemic lupus erythematosus. Overall, much progress has been made in elucidating the etiological agents and pathogenic mechanisms by which lupus develops. However, there is still some way to go before arriving at a unifying hypothesis. The reward for a better understanding of lupus immunopathogenesis will be the development of more specific targets for treatment, and the introduction of better and safer treatment modalities.