Lymphocyte apoptosis plays a central role in the pathophysiology of sepsis. Lymphocyte apoptosis was examined in mice with defective death receptor pathways due to transgenic expression of a dominant negative mutant of Fas-associated death domain (FADD-DN) or Bid^-/- and in mice with defective mitochondrial-mediated pathways due to loss of Bim^-/-, Puma^-/-, or Noxa^-/-. FADD-DN transgenic and Bid^-/- mice had significant albeit incomplete protection, and this protection was associated with increased survival. Surprisingly, splenic B cells were also protected in FADD-DN mice although transgene expression was confined to T cells, providing evidence for an indirect protective mechanism. Bim^-/- provided virtually complete protection against lymphocyte apoptosis whereas Puma^-/- and Noxa^-/- mice had modest or no protection, respectively. Bim^-/- mice had improved survival, and adoptive transfer of splenocytes from Bim^-/- mice into Rag 1^-/- mice demonstrated that this was a lymphocyte intrinsic effect. The improved survival was associated with decreased interleukin (IL) -10 and IL-6 cytokines. Collectively, these data indicate that numerous death stimuli are generated during sepsis, and it therefore appears unlikely that blocking a single "trigger" can inhibit apoptosis. If siRNA becomes practical therapeutically, proapoptotic proteins would be potential targets.--Chang, K. C., Unsinger, J., Davis, C. G., Schwulst, S. J., Muenzer, J. T., Strasser, A., Hotchkiss, R. S. Multiple triggers of cell death in sepsis: death receptor and mitochondrial-mediated apoptosis.