Cancer is an aging-related disease promoted by accumulation of cellular damage under stressful environment. Many natural products, known as chemopreventive compounds, can lower the risk of cancer by enhancing cellular capacity of handling stress. Studies of molecular targets of these compounds have led to the identification of a novel transcription factor Nrf2 that is a master regulator of a major cellular antioxidant response. The critical role of Nrf2 in chemoprevention has been recently established. Using small molecule Nrf2 activators for chemoprevention represents an innovative strategy for fighting against cancer. In this study, we demonstrated the feasibility of high-throughput screening of Nrf2 activators using a luriferase reporter gene assay as a primary screen. Hit confirmation was performed in a secondary screen based on immunodetection of the Nrfi protein. For bioefficacy study, compound-induced upregulation of hemeoxygenase I (HO-1) and NAD(P)H-quinone oxidoreductase (NQO1), two well studied Nrf2 target genes involved in the cellular antioxidant response, was detected using real time RT-PCR analysis. NQO1 enzymatic activity and intracellular glutathione level were assessed as the downstream effects of Nrf2 activation by these compounds. Although several Nrf2 activators have been identified using these approaches, it is time consuming and labor intensive. Development of sensitive devices for rapid, reliable, and high-throughput identification of Nrf2 activators will greatly speed up the identification of new drugs for chemoprevention.