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 spleno‐cytes from Bim^−/− mice into Rag 1^−/− mice demonstrated that this was a lymphocyte intrinsic effect. The improved survival was associated with decreased inter‐leukin (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 mitochondrialmediated apoptosis. FASEB J. 21, 708–719 (2007)