The transcription factor Nrf2 regulates the expression of important cytoprotective enzymes. Induction of cytochrome P450 2E1(CYP2E1) is one of the central pathways by which ethanol generates oxidative stress. CYP2E1 can be induced by ethanol and several low molecular weight chemicals such as pyrazole. The chapter discusses biochemical and toxicological effects of CYP2E1 and the effects of Nrf2 in modulating these actions of CYP2E1.Besides ethanol, CYP2E1 metabolizes and activates many other important toxicological compounds. One approach to try to understand basic effects and actions of CYP2E1 was to establish HepG2 cell lines that constitutively express human CYP2E1. Ethanol, polyunsaturated fatty acids and iron were toxic to the HepG2 cells which express CYP2E1 (E47 cells) but not control C34HepG2 cells which do not express CYP2E1.Toxicity was associated with enhanced oxidant stress and could be prevented by antioxidants and potentiated if glutathione (GSH) was removed. The E47 cells had higher GSH levels and a Twofold increase in catalase, cytosolic and microsomal glutathione transferase, and heme oxygenase-1 (HO-1) than control HepG2 cells due to activation of their respective genes. These activations were prevented by antioxidants, suggesting that reactive oxygen species (ROS) generated by CYP2E1 were responsible for the up-regulation of these antioxidant genes. This upregulation of antioxidant genes may reflect an adaptive mechanism to remove CYP2E1-derived oxidants. Increases in Nrf2 protein and mRNA were observed in livers of chronic alcohol-fed mice or rats and of pyrazole-treated rats or mice, conditions known to elevate CYP2E1. E47 cells showed increased Nrf2 mRNA and protein expression compared with control HepG2 C34 cells. Upregulation of antioxidant genes in E47 cells is dependent on Nrf2 and is prevented by siRNA-Nrf2. Blocking Nrf2 by siRNA-Nrf2 decreases GSH and increases ROS and lipid peroxidation, resulting in decreased mitochondrial membrane potential and loss of cell viability of E47 cells but not C34 cells. Nrf2 is activated and levels of Nrf2 protein and mRNA are increased when CYP2E1 is elevated. These results suggest that Nrf2 plays a key role in the adaptive response against increased oxidative stress caused by CYP2E1 in the HepG2 cells.