Protein S-thiolation/dethiolation, i.e., the oxidation of protein sulfhydryls to mixed disulfides and their reduction back to sulfhydryls, is an early cellular response to oxidative stress (1-5). This response may be elicited by oxidative phenomena of diverse origins, and the few cases that have been studied extensively give a limited insight into the metabolic roles and the molecular mechanism of the process. Much of our current understanding arose from experiences with isolated proteins containing "reactive" sulfhydryls (6, 7), but recent experiments at the cellular level have begun to reveal interesting insights that suggest a complexity and importance not appreciated previously (8). This article will discuss the current status of experiments that relate to both the role of the cellular process and to the reactivity of selected proteins that participate in the cellular processes. The discussion will center on the role of glutathione, a molecule of central interest in every aspect of protein S-thiolation and dethiolation.