Regulation of the homeostatic balance between cell proliferation and cell death is essential for development and maintenance of multicellular organisms. Physiologic, or programmed, cell death is dependent on a genetically encoded and evolutionarily conserved pathway that induces a form of cellular suicide known as apoptosis. In the past decade, it has become clear that the regulatory mechanisms controlling programmed cell death are as fundamental, and as complex, as those regulating cell proliferation. Perturbation of the signaling cascades regulating apoptosis, whether by extracellular triggers, acquired or germline genetic mutations, or viral mimicry of signaling molecules, can result in a wide variety of human diseases. Analysis of these regulatory pathways has led to a better understanding of the etiology and pathogenesis of many human diseases, notably cancers, infectious diseases including AIDS, autoimmune diseases, and neurodegenerative/neurodevelopmental diseases. Our understanding of the regulation of programmed cell death in health and disease is far from complete, and the challenge of converting that understanding into new therapeutic modalities has only begun to be approached.