Purpose: The selective killing of tumor cells is an important strategy for cancer therapeutics. The aim of this study was to develop a novel antitumor agent that is safe for normal cells with the ability to selectively target cancer cells. Experimental Design: On the basis of quantitative structure–activity relationship, we synthesized a novel polyphenol conjugate (E)-3-(3,5-dimethoxyphenyl)-1-(2-methoxyphenyl)prop-2-en-1-one (DPP-23). We evaluated the effect of DPP-23 on proliferation, cell cycle, and apoptosis in various tumor cells. We also assessed molecular targets of DPP-23 using genome-wide expression profiling by DNA microarray and real-time PCR array systems. Results: DPP-23 effectively inhibited the growth of cancer cells in vitro and in vivo (xenografts in Balb/c nude mice). At a molecular level, DPP-23 targeted the unfolded protein response (UPR) in the endoplasmic reticulum (ER) through the production of reactive oxygen species (ROS) in cancer cells, but not in normal cells, resulting in selective killing of tumor cells via caspase-dependent apoptosis. Conclusions: The selective generation of ROS in cancer cells could be an attractive strategy for the selective killing of cancer cells, while maintaining negligible cytotoxicity to normal cells. DPP-23 represents a promising novel therapeutic agent for the selective production of ROS in cancer cells. Clin Cancer Res; 20(16); 4302–13. ©2014 AACR.