Autoimmune diseases reflect the confluence of genetic, environmental and stochastic events. Recent studies have implicated apoptotic cell death pathways in initiating and propagating autoimmune diseases, as well as in rendering individuals susceptible to such diseases. Similar to autoimmunity, apoptosis is a multistep process, affecting immune and target cells, integrating numerous intrinsic and extrinsic signals, and requiring the actions of multiple gene products. Particularly relevant to the complexity of autoimmunity are the recent observations that apoptotic death might provide a primary source of tolerogen to shape the immune repertoire, or be the target of the immune response in autoimmunity, and that apoptosis is both required for lymphocyte selection and immunoregulation, and is a prominent outcome of immune and inflammatory effector pathways.