Electrophilic chemicals, pro-oxidants, heavy metals and cancer chemopreventive agents increase the expression of a range of cytoprotective proteins. The genes induced by these stressors include those for the antioxidant enzymes glutamate-cysteine ligase, glutathione peroxidase, thioredoxin, thioredoxin reductase, peroxiredoxin and sulfiredoxin, the drug-metabolising enzymes aldo-keto reductase, glutathione transferase, quinone reductase, and UDP-glucuronosyl transferase, and alpha and beta proteasome subunits (for a review see ref 1). Such genes are co-regulated through an antioxidant response element (ARE, 5′-TGACnnnGC-3′) present in their promoters (2,3). Studies in the mouse have shown that induction of ARE-driven genes by electrophiles and oxidants is mediated by the Nrf2 cap’n’collar bZIP transcription factor. Under normal homeostatic conditions Nrf2 has a relatively short half-life, but during redox stress it becomes relatively stable, and this is sufficient to allow induction of its target genes. The stress-dependent stabilization of Nrf2 is due to Keap1 (4), a redox-sensitive substrate adaptor for the E3 ubiquitin ligase Cul3/Rbx1 that is inactivated by various stressors (5,6). The functioning of Keap1 is central to understanding how Nrf2 mediates adaptation to stress. Thus, Nrf2 is normally rapidly ubiquitylated by Cul3/Rbx1 but during stress it evades ubiquitylation by Cul3/Rbx1. Preliminary data will be presented about how Keap1 senses a number of different types of stressors, and how this triggers an adaptive response. In particular, evidence will be presented that Keap1 contains three separate stress sensors, one of which appears to be specific for nitric oxide. Many researchers have shown that Nrf2 knockout mice are sensitive to chemical carcinogens, and that chemopreventive agents cannot protect them against carcinogenesis. Based on the hypothesis that Nrf2 knockout mice are unable to adapt to oxidative stress, we have tested whether the mutant mice are more sensitive to the development of non-alcoholic steatohepatitis (NASH) because the disease is thought to proceed in a two-step manner that involves i) insulin resistance, and ii) oxidative stress. Results will be presented showing that Nrf2-/- mice are markedly more sensitive than Nrf2+/+ at developing NASH when placed on a methionine- and choline-deficient diet (7).