Tumor necrosis factor‐α (TNF‐α) apoptosis by recruiting a complex of cytosolic proteins at its plasma membrane receptor. Among them is caspase‐8, an interleukin‐1β−converting enzyme (ICE)‐like protease that initiates an amplified protease cascade to activate the cell‐death machinery. The latter comprises at least caspase‐3 and caspase‐7, which execute cell death by cleaving numerous protein substrates, including poly(ADP‐ribose) polymerase. In addition, TNF‐α stimulates the production of ceramide, which also activates the death machinery. Whether the signaling pathways elicited by caspase‐8 and ceramide proceed independently or intersect at a specific subcellular site is unknown. Using the lysosomotropic agent NH₄Cl and the vesicularization inhibitor brefeldin A, we show here the convergence of TNF‐α‐induced death signaling on an acidic, subcellular compartment reminiscent of lysosomes. This compartment generates at least two signaling pathways that account for the caspase‐3 activation and apoptosis induced by TNFα, one involving ceramide and caspase‐unrelated adapter molecules and another involving yet unknown lysosomal mediators. The apoptosis inhibitor Bcl‐2 specifically acts on the ceramide‐activated pathway to block caspase‐3 activation and apoptosis. The latter result explains why Bcl‐2 only partially blocks TNF‐α‐induced apoptosis.