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TRAIL have been widely viewed as potential cancer therapeutics because of its specific apoptosis- inducing capacity in tumor cells. The increased understanding of apoptosis pathways has directed attention to components of death receptor mediated apoptotic pathway as potential targets not only for chemotherapeutic but also for chemopreventive agents. An increasing number of previously identified chemotherapeutic and chemopreventive agents were found to increase the sensitivity to TRAIL-mediated apoptosis in a variety of premalignant and malignant cell types in vitro and in a few animal models in vivo. Also, phase 1 and 2 clinical trials using agonistic mAb that engage the human TRAIL receptor DR4 and DR5 have also provided encouraging results in cancer patients. Thus, understanding the control of death receptor-mediated apoptosis by chemotherapeutic and chemopreventive agents and their implications in cancer treatments may provide a rational approach for using such agents alone or in combination with TRAIL to enhance TRAIL-mediated apoptosis. In this study, we summarize biological agent and drug that sensitize tumors to TRAIL-mediated apoptosis and discuss the potential molecular basis for their sensitization. (Cancer Prev Res 11, 9-21, 2006)