The free radical theory of aging proposes that the impairment in physiological performance associated with aging is caused by the detrimental effects of oxygen free radicals. This is interesting because it provides us with a theoretical framework to understand aging and because it suggests a rationale for intervention, i.e., antioxidant administration. Thus, the study of antioxidant systems of the cell may be very important in gerontological studies. Glutathione is one of the main nonprotein antioxidants in the cell which, together with its related enzymes, constitute the “glutathione system.” The involvement of glutathione in aging has been known since the early seventies. Several studies have reported that reduced glutathione is decreased in cells from old animals, whereas oxidized glutathione tends to be increased. Recent experiments from our laboratory have underscored the importance of cellular compartmentation of glutathione. Mitochondrial glutathione plays a key role in the protection against free radical damage associated with aging. Oxidative damage to mitochondrial DNA is directly related to an oxidation of mitochondrial glutathione. In fact, aging is associated with oxidative damage to proteins, nucleic acids, and lipids. These molecular lesions may be responsible for the low physiological performance of aged cells. Thus, antioxidant supplementation may be a rational way to partially protect against age-associated impairment in performance. Apoptosis, a programmed cell death, is an area of research which has seen an explosive growth. Glutathione is involved in apoptosis: apoptotic cells have lower levels of reduced glutathione, and administration of glutathione precursors prevent, or at least delay, apoptosis. Age-associated diseases constitute a major concern for researchers involved in aging. Free radicals are involved in many such diseases; for instance, cancer, diabetes or atherosclerosis. The key role of glutathione and other antioxidants in the pathophysiology of aging and age-associated diseases is discussed in this review.