Tumor necrosis factor a ( TNF-a) binding to the TNF receptor ( TNFR) potentially initiates apoptosis and activates the transcription factor nuclear factor kappa B (NF-kB), which suppresses apoptosis by an unknown mechanism. The activation of NF-kB was found to block the activation of caspase-8. TRAF1 ( TNFR-associated factor 1), TRAF2, and the inhibitor-of-apoptosis (IAP) proteins c-IAP1 and c-IAP2 were identified as gene targets of NF-kB transcriptional activity. In cells in which NF-kB was inactive, all of these proteins were required to fully suppress TNF-induced apoptosis, whereas c-IAP1 and c-IAP2 were sufficient to suppress etoposide-induced apoptosis. Thus, NF-kB activates a group of gene products that function cooperatively at the earliest checkpoint to suppress TNF-a–mediated apoptosis and that function more distally to suppress genotoxic agent–mediated apoptosis.