There have been many advances in the therapy of cancer following the introduction of cytotoxic chemotherapeutic drugs. Notable responses were observed in primary tumors and often in malignant metastatic tumors. However, one of the consequences of chemotherapy is the development/acquisition of drug-resistant phenotypes and the development of multiple drug resistance. The development of drug resistance remains a major obstacle in the treatment of such tumors and therefore, there is an obvious need for alternative approaches such as immune/gene therapy. The cloning of biologically active cytotoxic molecules has been considered as potential new therapeutics in the destruction of drug-resistant tumor cells. For instance, some members of the TNF-superfamily are characterized by their ability to inflict cell death upon binding to their cognate receptors. TNF-alpha was the first molecule to be tested for its anti-tumor activity, followed by Fas-ligand. These two molecules are efficient in killing a variety of tumor cells, however, they cause significant damage to normal tissues that result in life-threatening toxicities. Therefore, the search for a cytotoxic molecule that is selective for tumor cells has continued until the recently discovered new member of the TNF superfamily, namely TRAIL/APO-2L. TRAIL has been shown to be selectively cytotoxic in inducing apoptosis against tumor cells and has minimal or no toxicity against normal tissues, as examined both in vitro and in vivo in mice. Therefore, TRAIL is a new agent that has great potential for its in vivo anti-cancer effect, whether used alone or in combination with drugs. Studies from our laboratory have recently demonstrated that tumor cells that are resistant to TRAIL can be sensitized by subtoxic concentrations of drugs/cytokines and the sensitized tumor cells are significantly killed by TRAIL. This review describes the current status of research studies performed with TRAIL by other investigators as well as by our laboratory.