Glutathione has multiple metabolic actions that are essential for cellular homeostasis. In spite of this important role in cellular physiology, disease states due to glutathione deficiency are not common. The participation of both tissue and circulating glutathione deficiency in disease pathogenesis is likely to be subtle and not easily defined. Despite these difficulties, a number of inherited conditions of glutathione deficiency are known, and acquired ones are being identified. Examples of the acquired deficiency state include idiopathic pulmonary fibrosis, human immunodeficiency virus-related disease, and respiratory distress syndrome. Much of our current understanding of the utility of glutathione supplementation in states of tissue injury is derived from biochemical, animal, and cell culture studies. In this article we will review what is known about glutathione deficiency states and explore strategies by which tissue glutathione levels might be maintained or increased to prevent tissue injury and disease. © 1994.