Adaptation to oxidative and nitrosative stress occurs in cells first exposed to a nontoxic stress, resulting in the ability to tolerate a toxic challenge of the same or a related oxidant. Adaptation is observed in a wide variety of cells including endothelial cells on exposure to nitric oxide or oxidized lipids, and lung epithelial cells exposed to air-borne pollutants and toxicants. This acquired characteristic has been related to the regulation of a family of stress responding proteins including those that control the synthesis of the intracellular antioxidant glutathione. The focus of this article, which includes a review of recent results along with new data, is the regulation and signaling of glutathione biosynthesis, especially those relating to adaptive mechanisms. These concepts are illustrated with examples using nitric oxide and oxidized low density lipoprotein mediated adaptation to oxidative stress. These data are discussed in the context of other adaptive mechanisms relating to glutathione synthesis including those from dietary constituents such as curcumin.