Apoptosis and the subsequent removal of apoptotic cells underpin a healthy immune system. They are crucial for both the maintenance of self-tolerance and the contraction of clonally expanded lymphocytes at the conclusion of immune responses. Aberrant apoptosis and the disposal of apoptotic cells is implicated in the development of both systemic and organ-specific autoimmune disease and is a major contributing factor in disease susceptibility. Dissection of the molecular mechanisms involved in dysregulated apoptosis may reveal pathways which can be targeted for more effective therapeutic intervention. This review highlights the molecular events underlying programmed cell death and apoptotic cell uptake, and summarizes recent studies that link impaired apoptotic death to autoimmunity.