In the immune system, lymphocyte activation by antigen is followed by cell proliferation and induction of effector functions. Subsequently, physiologic cell-death signals are induced, resulting in removal of expanded effector-cell populations, to maintain homeostasis. Caspases are intracellular participants in both activation responses and cell death by apoptosis. Targets of caspases include inflammatory activators and also other members of the caspase family that mediate apoptosis. Caspase-8 and caspase-10 participate in the protease cascade following cell surface CD95 engagement by its ligand. Humans with defects in these caspases were initially evaluated for the autoimmune lymphoproliferative syndrome because of their spleen and lymph node enlargement. Although both caspase-8- and caspase-10-deficient individuals had impaired apoptosis, those with caspase-8 deficiency, who also had immunodeficiency, had additional defects in activation of lymphocytes and natural killer cells. These disorders help to define the importance and specificity of the caspase proteases in intracellular signaling pathways.