It is not surprising that the recent explosion of interest in physiological cell death has been centered particularly on lymphocytes. Physiological cell death responses are singularly important in the biology of T lymphocytes, especially in the establishment and maintenance of a diverse, non-autoreactive, and self-limiting repertoire. Cell death responses can be triggered in T cells by a variety of stimuli; sensitivity to these inducers is altered as a function of differentiation, activation, aging, and transformation. The elimination of autoreactive T cells occurs by a process that involves comitogenic stimulation at high dose with antigenic and/or mitogenic agents. The control of susceptibility to this activation-driven cell death with differentiation and with prior activation provides a mechanistic explanation for the development of central and peripheral tolerance. Enhanced lymphocyte activation with aging also leads to an augmented activation-driven cell death response. However, aging does not alter cell death responses generally, and aging-associated changes in cell death responses cannot account for aging-associated immunopathology. Oncogenic transformation also alters the activation-driven cell death response by supplanting one of the required signals for activation-driven cell death. This difference provides a rationale for selective anti-tumor therapy. A single mechanism underlies all cases of physiological cell death and involves out-of-phase mitotic activity. We now know that of the two hallmarks of cell death, genome digestion is dispensable and mitotic-like events associated with cell cycle arrest are critical. T cells triggered to undergo physiological cell death arrest in a post-mitotic compartment of the cell cycle and die when they attempt a precocious and abortive mitosis.