It is becoming increasingly clear that most mammalian cells are capable of undergoing apoptosis and that, within particular lineages, specific apoptotic pathways have evolved to regulate survival and turnover. The role of apoptosis in the megakaryocyte lineage is an intriguing one. Various insults, such as chemotherapeutics, autoantibodies, and human immunodeficiency virus (HIV), have been suggested to induce the apoptotic death of megakaryocytes and/or their progenitors. Conversely, apoptotic processes have been implicated in megakaryocyte development and platelet production. Platelets also contain functional apoptotic pathways, which circumscribe their survival. It has even been suggested that platelet activation responses involve components of the apoptotic machinery, highlighting a potential role for apoptotic processes in hemostasis and thrombosis. This review discusses the current state of knowledge about how apoptosis and apoptotic proteins contribute to the generation and function of megakaryocytes and platelets.