The therapeutic use of TRAIL as an inducer of tumor specific cell death prove to be an useful strategy to overcome resistant of cancer cells to conventional chemotherapeutic agents. Although five death receptors have been identified which bind TRAIL and a number of checkpoint involved in TRAIL pathway are known, the molecular mechanism underlying the resistant or sensitivity of normal/transformed cells remains poorly understood. The key to the clinical use of TRAIL is that normal cells are resistant to its cytotoxic activity and that it specifically targets cancer cells thus resulting in large therapeutic index. In spite of this observation, TRAIL will probably not be viable as single agent as there are numerous reports that have demonstrated the resistance of various tumor cells to TRAIL. The concept of combination therapy is therefore key for the use of TRAIL against tumors that are refractory to treatment with either agent alone. Results from preclinical studies on TRAIL have been very promising for cancer treatment; however, outcome from phase I/II clinical trials is eagerly awaited to assess its safety. Only time will tell whether the search for the Holy Grail for treatment of cancer will end with TRAIL?