NF-κB inhibition enhances apoptosis induced by TNF, ionizing radiation, and daunorubicin. The activation of NF-κB by these agents protects cells from apoptosis. Inhibition of NF-κB nuclear translocation increases apoptotic killing. This suggests that NF-κB is involved in cellular resistance to apoptosis. NF-κB may have an anti-apoptotic role, as mice lacking the p65/RelA gene die from liver apoptosis. HT1080 cells, resistant to TNF, were used to study NF-κB's role. A super-repressor IκBα was expressed to block NF-κB activation. TNF-induced apoptosis was enhanced in these cells. TUNEL assay confirmed apoptosis. IL-1 pretreatment blocked TNF-induced apoptosis in HT1080V cells but not in HT1080I cells. Proteasome inhibitors enhanced TNF-induced apoptosis. NF-κB subunits restored protection against TNF-induced apoptosis. Embryonic fibroblasts from RelA/p65 null mice were more susceptible to TNF. NF-κB activation by ionizing radiation, daunorubicin, and staurosporine was blocked in HT1080I cells. Apoptosis induced by these agents was enhanced in HT1080I cells. NF-κB activation protects against apoptosis. TNF, ionizing radiation, and daunorubicin activate NF-κB, which protects cells from apoptosis. NF-κB does not induce apoptosis. Apoptosis is initiated by ceramide production. NF-κB activation inhibits apoptosis. NF-κB may have pro-apoptotic functions in some conditions. NF-κB inhibition enhances apoptosis. NF-κB inhibition may improve cancer therapy. NF-κB inhibition combined with standard therapies may enhance cancer treatment. Glucocorticoids inhibit NF-κB and may enhance chemotherapy. NF-κB inhibition lowers the anti-apoptotic threshold of tumors. NF-κB inhibition with TNF treatment may enhance antitumor effects. NF-κB inhibition may improve cancer therapy.NF-κB inhibition enhances apoptosis induced by TNF, ionizing radiation, and daunorubicin. The activation of NF-κB by these agents protects cells from apoptosis. Inhibition of NF-κB nuclear translocation increases apoptotic killing. This suggests that NF-κB is involved in cellular resistance to apoptosis. NF-κB may have an anti-apoptotic role, as mice lacking the p65/RelA gene die from liver apoptosis. HT1080 cells, resistant to TNF, were used to study NF-κB's role. A super-repressor IκBα was expressed to block NF-κB activation. TNF-induced apoptosis was enhanced in these cells. TUNEL assay confirmed apoptosis. IL-1 pretreatment blocked TNF-induced apoptosis in HT1080V cells but not in HT1080I cells. Proteasome inhibitors enhanced TNF-induced apoptosis. NF-κB subunits restored protection against TNF-induced apoptosis. Embryonic fibroblasts from RelA/p65 null mice were more susceptible to TNF. NF-κB activation by ionizing radiation, daunorubicin, and staurosporine was blocked in HT1080I cells. Apoptosis induced by these agents was enhanced in HT1080I cells. NF-κB activation protects against apoptosis. TNF, ionizing radiation, and daunorubicin activate NF-κB, which protects cells from apoptosis. NF-κB does not induce apoptosis. Apoptosis is initiated by ceramide production. NF-κB activation inhibits apoptosis. NF-κB may have pro-apoptotic functions in some conditions. NF-κB inhibition enhances apoptosis. NF-κB inhibition may improve cancer therapy. NF-κB inhibition combined with standard therapies may enhance cancer treatment. Glucocorticoids inhibit NF-κB and may enhance chemotherapy. NF-κB inhibition lowers the anti-apoptotic threshold of tumors. NF-κB inhibition with TNF treatment may enhance antitumor effects. NF-κB inhibition may improve cancer therapy.