Programmed cell death is essential for the development and maintenance of cellular homeostasis of the immune system. The Bcl-2 family of proteins comprises both pro-apoptotic and anti-apoptotic members. A subset of pro-apoptotic members, called 'BH3-only' proteins, share sequence homology only in the minimal death domain, designated the Bcl-2 homology 3 (BH3) domain. BH3-only proteins operate as upstream sentinels, selectively sensing both intrinsic and extrinsic death stimuli. They communicate this information to the pro-apoptotic 'multidomain' members Bax or Bak--a process that is antagonized by anti-apoptotic members of the Bcl-2 family. The functional balance of pro-apoptotic versus anti-apoptotic influences, which operates at organelles, determines whether a lymphocyte will live or die. BH3-only molecules, often working in concert, compete for downstream multidomain pro- and anti-apoptotic BCL-2 members to control serial stages of lymphocyte development and homeostasis.