In cancer therapy outgrowth of chemoresistant tumor cells is the most important factor that ultimately determines-apart from immediate adverse effects during treatment-the life span and prognosis of cancer patients. Despite many advances in cancer treatment and the integration of supportive medications, including new and better drugs for pain management, antiemesis, infection, and reconstitution of the hematopoietic system, both toxic effects and the development of resistance in response to the treatment remain a major problem. New treatment regimens have to be developed to target cancer more specifically using multiple cellular pathways. This will reduce toxic effects as well as the development of chemoresistance. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is the ligand for death receptors that belong to the TNF death receptor family. TRAIL triggers apoptosis in vitro in various cancer cell types. The antitumor drug, Paclitaxel (PA) was shown to increase the survival of patients with cancer. In in vitro experiments, PA also induces apoptosis in cancer cells. Together, PA and TRAIL lead to tumor regression in in vivo therapy and induce apoptosis through the interaction of TNF family death receptors, caspase activation, and?or cytochrome c release from mitochondria. PA and TRAIL complement each other using two distinct pathways that trigger apoptosis in addition to the anti-microtubule effect of PA. The combination of TRAIL and PA suppresses tumor growth that is otherwise resistant to treatment with either PA or TRAIL alone, by improving proapoptotic effects of the drugs. This observation support the use of the PA and TRAIL in future clinical trials.