Treatment of cancer patients with conventional therapies (chemotherapy, hormonal therapy, immunotherapy and radiation) respond initially well and experience prolonged tumor-free survival. However, in many patients tumor recurrences and relapses occur and such tumors exhibit the resistant phenotype i.e. cross-resistance to various cytotoxic and apoptotic agents. Therefore, new therapeutic strategies are currently being explored and are based on a better understanding of the underlying biochemical and molecular mechanisms of tumor cell resistance. Hence, novel sensitizing agents that can modify the tumor dysregulated apoptotic gene products can reverse resistance when used in combination with subtoxic doses of cytotoxic reagents. Targeted anti-tumor therapies are the current choice in the treatment of resistant tumors. One such targeted therapy is the application of TRAIL or TRAIL agonist monoclonal antibodies (mAbs) (anti-DR4 and anti-DR5) because, unlike Fas ligand and TNF-alpha, they are not cytotoxic to normal tissues. TRAIL as monotherapy will only be effective against TRAIL sensitive tumors, however, most tumors are resistant to TRAIL and their sensitization can restore their sensitivity to TRAIL apoptosis. We present, herein, one potential novel sensitizing agent, namely, nitric oxide (NO) that has been shown to sensitize TRAIL-resistant tumor cells to TRAIL apoptosis via its inhibitory effect on the transcription factors NF-kappaB and Yin Yang 1 (YY1), concomitantly with upregulation of DR5. We propose the therapeutic application of NO donors as sensitizing agents used in combination with TRAIL/DR4 or DR5 mAbs in the treatment of TRAIL-resistant tumors.