This scheme is based upon data from the studies summarized in this article, which provide a mechanistic framework for pathways that regulate intracellular Nrf2-ARE responses. Under basal conditions, Nrf2 is mainly localized to the cytosol and undergoes Keap1-mediated, ubiquitin (Ubq)-dependent proteosomal degradation. In the inducible state, toxicants or proxidants disrupt the interaction between Nrf2 and Keap1, either directly or indirectly through the generation of elevated levels of ROS by NADPH oxidase or mitochondria, thereby facilitating nuclear accumulation of Nrf2. Upon dimerization with the MAF, JUN, or ATF family of proteins, Nrf2 binds to the ARE sequence. This binding promotes or favors the displacement of negative factors, such as the Bach and Fos proteins, that bind to the ARE and the subsequent recruitment of transcriptional co-activators such as CBP/p300. The activation of kinases (PKC and MAP kinases) by toxicants affects both the nuclear accumulation and recruitment of Nrf2 and other transcription factors that bind at the ARE. Late induction of Fos proteins, such as Fra1, or modification of Bach proteins by oxidative stress and their subsequent nuclear accumulation dampens the ARE-mediated transcriptional activation either by competition with Nrf2 or displacement of Nrf2 from the promoter. Exportin Crm1 (CRM) and Keap1 facilitate the export of Nrf2 from the nucleus to the cytoplasm, where the latter undergoes Ubq-mediated degradation. M/J/A represents the MAF, JUN, or ATF protein. The double arrow indicates the position of the TRE-like AP-1 binding sequence. p, phosphorylation; M, modification such as oxidation.