Many cells are resistant to stimuli that can induce apoptosis, but the mechanisms involved are not fully understood. The activation of the transcription factor nuclear factor-kappa B (NF-κB) by tumor necrosis factor (TNF), ionizing radiation, or daunorubicin (a cancer chemotherapeutic compound), was found to protect from cell killing. Inhibition of NF-κB nuclear translocation enhanced apoptotic killing by these reagents but not by apoptotic stimuli that do not activate NF-κB. These results provide a mechanism of cellular resistance to killing by some apoptotic reagents, offer insight into a new role for NF-κB, and have potential for improvement of the efficacy of cancer therapies.