Caspase-8, an aspartate-specific cysteine protease, is best known for its ability to activate cell death via death receptors such as CD95 (Fas/Apo1). Recent evidence indicates that caspase-8 also has non-apoptotic functions in the transduction of signals via T-cell, B-cell and Toll-like receptors on lymphocytes. Previously, the in vivo role of caspase-8 has eluded analysis in post-natal tissues due to embryonic lethality associated with its deletion in mice. To circumvent embryonic lethality we generated mice with targeted caspase 8 disruption that is restricted to T-lymphocytes (tcasp8 -/-). Caspase-8 ablation protected T-lymphocytes from CD95 ligand but not anti-CD3 induced apoptosis, or apoptosis activated with agents that are known to act through the mitochondria. Importantly, these mice manifested a decrease in the number of peripheral T-cells and impaired activation induced T-cell proliferation (AITP). Caspase 8 mutant mice were unable to mount an immune response to viral infection, indicating that caspase 8 deletion in T-cells leads to immunodeficiency. Furthermore, mice lacking caspase-8 in T-cells developed a lethal, age dependent lymphoproliferative and lymphoinfiltrative immune disorder. With age, tcasp8 -/- mice developed lymphoadenopathy, splenomegaly and accumulated non-clonal T-cell infiltrates in lung, liver and kidneys accompanied by tissue damage. Casp8-/- T-cells isolated from old mice were in a perpetual state of activation in the absence of any infection or stimulation, which could account for the observed pathological phenotypes. These findings identify an essential, cell stage-specific role for caspase 8 in T-cell homeostasis and T-cell mediated immunity. Also, these studies uncover novel physiological functions for caspase-8 in immune regulation and function.