The article reviews the role of nuclear factor erythroid 2-related factor 2 (Nrf2) in oxidative stress and toxicity. Nrf2 is a transcription factor that regulates the expression of antioxidant response element (ARE)-dependent genes, which play a crucial role in protecting cells from oxidative damage. The review discusses how Nrf2 senses oxidants and activates antioxidant defense systems, including the induction of drug-metabolizing enzymes and antioxidant proteins. Nrf2 is regulated by a complex signaling pathway involving its interaction with Keap1, a negative regulator. Oxidants can modify Keap1 and Nrf2, leading to their activation and subsequent induction of ARE genes. The review also explores the evolutionary conservation of Nrf2 signaling, its impact on various physiological functions such as autophagy, inflammation, and stem cell function, and its role in toxicity and disease, including acetaminophen hepatotoxicity, ethanol-induced liver disease, cigarette smoke-induced chronic obstructive pulmonary disease (COPD), and cancer. Overall, the article highlights the multifaceted role of Nrf2 in maintaining cellular redox homeostasis and protecting against oxidative stress and toxicity.The article reviews the role of nuclear factor erythroid 2-related factor 2 (Nrf2) in oxidative stress and toxicity. Nrf2 is a transcription factor that regulates the expression of antioxidant response element (ARE)-dependent genes, which play a crucial role in protecting cells from oxidative damage. The review discusses how Nrf2 senses oxidants and activates antioxidant defense systems, including the induction of drug-metabolizing enzymes and antioxidant proteins. Nrf2 is regulated by a complex signaling pathway involving its interaction with Keap1, a negative regulator. Oxidants can modify Keap1 and Nrf2, leading to their activation and subsequent induction of ARE genes. The review also explores the evolutionary conservation of Nrf2 signaling, its impact on various physiological functions such as autophagy, inflammation, and stem cell function, and its role in toxicity and disease, including acetaminophen hepatotoxicity, ethanol-induced liver disease, cigarette smoke-induced chronic obstructive pulmonary disease (COPD), and cancer. Overall, the article highlights the multifaceted role of Nrf2 in maintaining cellular redox homeostasis and protecting against oxidative stress and toxicity.