The study investigates the distinct caspase cascades involved in receptor-mediated and chemical-induced apoptosis. It demonstrates that both types of apoptosis result in a similar time-dependent activation of caspases-3, -7, -8, and -9 in Jurkat T cells and human leukemic U937 cells. However, the inhibition of apoptosis by the caspase inhibitor Z-VAD.FMK occurs at different stages in the two processes. In receptor-mediated apoptosis, Z-VAD.FMK inhibits apoptosis prior to commitment to cell death by blocking the upstream activator caspase-8, cleavage of Bid, release of mitochondrial cytochrome c, processing of effector caspases, loss of mitochondrial membrane potential, and externalization of phosphatidylserine. In contrast, in chemical-induced apoptosis, Z-VAD.FMK inhibits apoptosis after commitment to cell death by blocking the initiator caspase-9 and the resultant postmitochondrial activation of effector caspases. Cleavage of Bid but not release of cytochrome c is blocked by Z-VAD.FMK, indicating that in chemical-induced apoptosis, cytochrome c release is caspase-independent and not mediated by activation of Bid. The study proposes that caspases form an integral part of the cell death-inducing mechanism in receptor-mediated apoptosis, whereas in chemical-induced apoptosis they act solely as executioners of apoptosis. The findings highlight the differences in the activation and regulation of caspase cascades in these two forms of apoptosis.The study investigates the distinct caspase cascades involved in receptor-mediated and chemical-induced apoptosis. It demonstrates that both types of apoptosis result in a similar time-dependent activation of caspases-3, -7, -8, and -9 in Jurkat T cells and human leukemic U937 cells. However, the inhibition of apoptosis by the caspase inhibitor Z-VAD.FMK occurs at different stages in the two processes. In receptor-mediated apoptosis, Z-VAD.FMK inhibits apoptosis prior to commitment to cell death by blocking the upstream activator caspase-8, cleavage of Bid, release of mitochondrial cytochrome c, processing of effector caspases, loss of mitochondrial membrane potential, and externalization of phosphatidylserine. In contrast, in chemical-induced apoptosis, Z-VAD.FMK inhibits apoptosis after commitment to cell death by blocking the initiator caspase-9 and the resultant postmitochondrial activation of effector caspases. Cleavage of Bid but not release of cytochrome c is blocked by Z-VAD.FMK, indicating that in chemical-induced apoptosis, cytochrome c release is caspase-independent and not mediated by activation of Bid. The study proposes that caspases form an integral part of the cell death-inducing mechanism in receptor-mediated apoptosis, whereas in chemical-induced apoptosis they act solely as executioners of apoptosis. The findings highlight the differences in the activation and regulation of caspase cascades in these two forms of apoptosis.