Sepsis is characterized by severe redox imbalance. Glutathione plays a major role in cellular defenses against oxidative and nitrosative stress. There is limited information on the response of glutathione synthesis in human sepsis. This review proposes a critical analysis of available data on potential factors affecting glutathione synthesis in sepsis. Glutathione is synthesized from its constituent amino acids—glutamate, cysteine, and glycine. Cysteine availability and the activity of the enzyme glutamate cysteine ligase are rate-limiting for glutathione synthesis. Glutathione synthetic capacity is increased in liver and other tissues during the acute phase of experimental sepsis. Potential mechanisms for glutamate cysteine ligase activation in sepsis involve a decreased ratio of reduced/oxidized glutathione as well as the effects of reactive oxygen species, nitric oxide species, proinflammatory cytokines, heat shock proteins, and physical inactivity. Glutathione synthesis can be impaired by cysteine depletion, protein-energy malnutrition, hyperglycemia, glucocorticoid at pharmacologic doses, and decreased secretion of anterior pituitary hormones (growth hormones, thyrotropin, gonadotropins), as often observed in prolonged critical illness.