Accumulating epidemiological and clinical evidence shows that chronic inflammation plays a critical role in neoplastic transformation and progression. Long-term users of selective cycloxygenase-2 (Cox-2) inhibitors (coxibs) and non-steroidal anti-inflammatory drugs (NSAIDs) have been reported to have a reduced risk of developing colorectal cancer. However, the adverse gastrointestinal and cardiovascular side effects associated with these drugs have limited their routine use for cancer chemoprevention. Basic leucine zipper (bZIP) protein Nrf2, a key transcription factor mediating the antioxidant response is an important modulator of tumor susceptibility in mouse models. Mice lacking Nrf2 are more susceptible to carcinogenesis induced by carcinogens. Moreover, induction of the Nrf2 signaling pathway is essential for many food phytochemicals to exert their cancer chemopreventive activity as demonstrated in many preclinical studies. It has been recently shown that the combination of coxibs or NSAIDs and natural phytochemicals can synergistically inhibit carcinogenesis in rodent models. This review will focus on the role of chronic inflammation and the Nrf2 signaling pathway in carcinogenesis and the feasibility of targeting these signaling pathways with dietary cancer chemopreventive agents and for cancer chemoprevention.