Nrf2 activation is central to cytoprotective gene expression against oxidative and/or electrophilic stress. Unless activated by inflammatory, environmental, or oxidative stressors, Nrf2 is sequestered in the cytoplasm by its repressor, Keap1. Because of its protective capabilities, small molecules that activate Nrf2 signaling are being examined as potential anti-cancer or anti-inflammatory agents. 2-Trifluoromethyl-2'-methoxychalcone is a potent activator of Nrf2, both in vitro and in mice. Human bronchial epithelial cells treated with 10 μM 2-trifluoromethyl-2'-methoxychalcone showed a marked increase in the expression of the Nrf2-regulated antioxidant genes, GCLM and NQO1. Furthermore, treatment of mice with 50 mg/kg 2-trifluoromethyl-2’-methoxychalcone leads to a 4.5- and 4.6-fold increase in the expression of GCLM and NQO1, respectively, in the small intestine.