Glutathione (L-γ-glutamyl-L-cysteinyl-glycine; GSH) is the most abundant low molecular weight thiol in animal cells, and plays a crucial role in cellular defenses against oxidative stress. This tripeptide is synthesized in many cell types from L-glutamate, L-cysteine and glycine by γ - glutamylcysteine synthetase (γ -GCS) and GSH synthetase in the cytosol. γ-GCS and cysteine are the rate-controlling enzyme and limiting substrate, respectively, in de novo GSH synthesis. Liver is quantitatively the major organ for GSH synthesis in animals, and releases GSH either intact or as γ-Glu-(Cys)₂ due to γ-glutamyl transpeptidase activity on the outer plasma membrane. There is little uptake of GSH or glutathione disulfide by cells due to an energetically unfavorable concentration gradient (e.g., intracellular [GSH] =0.5-10 mM; plasma [GSH] = 5 -50 μM). However, γ-Glu-(Cys)₂ and Cys-Gly [derived from GSH and (Cys)₂] are readily taken up by extrahepatic cells, where they are utilized for GSH synthesis. Maintenance of intracellular GSH concentrations, which depend on the balance between its synthesis and utilization, is crucial for cell integrity and function as well as the removal of free radicals and reactive oxygen /nitrogen species. Recent studies have established a link between a cellular GSH deficiency and the pathogenesis of many diseases, including kwashiorkor (predominantly protein deficiency), seizure, Alzheimer`s disease, Parkinson`s disease, sickle cell anemia, AIDS, and chronic diseases associated with ageing and infection. A better understanding of the nutritional regulation of GSH synthesis is critical to developing effective strategies to prevent the vicious cycle of malnutrition and disease.