Studies of antinuclear autoantibodies (ANAs) associated with systemic autoimmune diseases and their target autoantigens have revealed several key features of the nature of the ANA response. First, each systemic autoimmune disease has a characteristic ANA spectrum, suggesting that specific inciting antigens must be associated with each disease. Second, ANAs are directed against components of functionally important subcellular particles. Third, ANAs recognize highly conserved, conformation-dependent epitopes associated with active regions of the targeted subcellular particle. Fourth, ANAs often target autoantigens associated with active cell division or proliferation. These features support the hypothesis that ANAs are driven by subcellular particles such as organelles or macromolecular complexes which might be in an activated or functional state. This hypothesis leads to the central question of how endogenous subcellular particles that are normally sequestered can be released from cells and exposed to the immune system in a manner that renders them capable of driving a sustained ANA response. An emerging view is that apoptosis could be a mechanism by which potentially immunostimulatory self-antigens might be released from cells. Unregulated cell death or aberrant phagocytic clearance and presentation of debris from dying cells might facilitate the exposure to the immune system of excessive amounts of intracellular material which could potentially induce and maintain, by repeated stimulation, an ANA response.