Activation of NFkappaB is frequently associated with human malignancies. The involvement of NFkappaB is in part attributed to its ability to activate various genes promoting cell survival. This property contributes to aggressive tumor growth and resistance to chemotherapy and radiation in cancer treatment. Various reports have shown that inhibition of NFkappaB promotes apoptosis and suppress tumor growth. However, NFkappaB has many important cellular functions and targeting NFkappaB directly may lead to severe side effects. Thus, developing strategies with low cytotoxicity to overcome NKkappaB-mediated cell survival is critical to improve cancer therapy. In this report, we described an approach using TRAIL/ Apo2L (TNF-related apoptosis-inducing ligand TRAIL or Apo2 ligand) and a Smac analog to overcome and bypass NFkappaB activation in cancer treatment. We have shown that a panel of head and neck squamous cell carcinoma (HNSCC) cell lines are highly resistant to TRAIL-induced apoptosis due to activation of NFkappaB-mediated cell survival pathways, and that inhibition of NFkappaB renders HNSCC cells sensitive to TRAIL. We further show that TRAIL and a small molecule mimic of Smac overcome and bypass NFkappaB activation in inducing cancer cell death. Since this treatment has no effect on NFkappaB activation and TRAIL offers tumor selectivity, cotreatment of TRAIL and Smac provides a strategy with potentially low toxicity to overcome NFkappaB activation in cancer cells, which has potential therapeutic benefit.