Systemic lupus erythematosus (SLE) is prototypic autoimmune disease characterized by the production of autoantibodies to DNA among other nuclear molecules. These antibodies can form immune complexes that promote pathogenesis by stimulating cytokine production and depositing in the kidney to instigate nephritis. The antigens that form these complexes arise from the blood nucleome, a pool of circulating macromolecules comprised of DNA, RNA and nuclear proteins released from cells. Cell death is a major source of these molecules, releasing DNA in a process that can be modeled in mice by the administration of cells killed ex vivo. In the mouse model, the appearance of blood DNA requires macrophages and differs between males and females. This finding raises the possibility that augmented levels of extracellular DNA and other nuclear antigens can contribute to the increased frequency of SLE in females. Extracellular DNA can occur in both a soluble and particulate form, with microparticles generated in vitro displaying antigenically active DNA. Together, these findings suggest that cell death is an important event in lupus pathogenesis and can provide a supply of blood DNA essential for immune complex formation.