XIAP prevents apoptosis by binding to and inhibiting caspases, and this inhibition can be relieved by IAP antagonists, such as Smac/DIABLO. IAP antagonist compounds (IACs) have therefore been designed to inhibit XIAP to kill tumor cells. Because XIAP inhibits postmitochondrial caspases, caspase 8 inhibitors should not block killing by IACs. Instead, we show that apoptosis caused by an IAC is blocked by the caspase 8 inhibitor crmA and that IAP antagonists activate NF-κB signaling via inhibtion of cIAP1. In sensitive tumor lines, IAP antagonist induced NF-κB-stimulated production of TNFα that killed cells in an autocrine fashion. Inhibition of NF-κB reduced TNFα production, and blocking NF-κB activation or TNFα allowed tumor cells to survive IAC-induced apoptosis. Cells treated with an IAC, or those in which cIAP1 was deleted, became sensitive to apoptosis induced by exogenous TNFα, suggesting novel uses of these compounds in treating cancer.