This review focuses on the role of crucial cellular nucleophiles, such as glutathione (GSH), and their interaction with oxidants and other critical enzymes like peroxiredoxins. It discusses the importance of the Nrf2-Keap1 pathway as an example of a transcriptional antioxidant response and summarizes transcriptional routes related to redox activation. The review highlights endoplasmic reticulum (ER) stress and ischemia-reperfusion as pathophysiological settings where antioxidant responses play major roles. Topologically confined redox-mediated post-translational modifications of thiols are considered important molecular mechanisms mediating many antioxidant responses, while redox-sensitive microRNAs have emerged as key players in the posttranscriptional regulation of redox-mediated gene expression. Understanding these mechanisms may provide the basis for antioxidant-based therapeutic interventions in redox-related diseases.This review focuses on the role of crucial cellular nucleophiles, such as glutathione (GSH), and their interaction with oxidants and other critical enzymes like peroxiredoxins. It discusses the importance of the Nrf2-Keap1 pathway as an example of a transcriptional antioxidant response and summarizes transcriptional routes related to redox activation. The review highlights endoplasmic reticulum (ER) stress and ischemia-reperfusion as pathophysiological settings where antioxidant responses play major roles. Topologically confined redox-mediated post-translational modifications of thiols are considered important molecular mechanisms mediating many antioxidant responses, while redox-sensitive microRNAs have emerged as key players in the posttranscriptional regulation of redox-mediated gene expression. Understanding these mechanisms may provide the basis for antioxidant-based therapeutic interventions in redox-related diseases.