Advances in genetics and new understanding of the molecular pathways that mediate innate and adaptive immune system activation, along with renewed focus on the role of the complement system as a mediator of inflammation, have stimulated elaboration of a scheme that might explain key mechanisms in the pathogenesis of systemic lupus erythematosus. Clinical observations identifying important comorbidities in patients with lupus have been a recent focus of research linking immune mechanisms with clinical manifestations of disease. While these advances have identified rational and promising targets for therapy, so far the therapeutic trials of new biologic agents have not met their potential. Nonetheless, progress in understanding the underlying immunopathogenesis of lupus and its impact on clinical disease has accelerated the pace of clinical research to improve the outcomes of patients with systemic lupus erythematosus.