Glutathione (GSH) is the most abundant nonprotein thiol found in living organisms. Since its discovery 130 years ago, understanding its cellular functions has been the subject of intensive research. Common scientific knowledge states that GSH is a major nonenzymatic antioxidant and redox buffer. Recent approaches that consider GSH compartmentation in the eukaryotic cell challenge this traditional view and reveal novel unexpected insights into GSH metabolism and physiology. This Forum on GSH features six review articles that focus on GSH metabolism and functions in mitochondria and the endoplasmic reticulum; its connection to cellular iron homeostasis, carcinogenesis, and anticancer drug resistance; a revisited view of GSH degradation pathways; and reconsiders old concepts of its mode of action by highlighting the importance of kinetics over thermodynamic redox equilibria. Antioxid. Redox Signal. 27, 1127–1129.