Glutathione plays a critical role in many biological processes both directly as a co-factor in enzymatic reactions and indirectly as the major thiol-disulfide redox buffer in mammalian cells. Glutathione also provides a critical defense system for the protection of cells from many forms of stress. However, mild stress generally increases glutathione levels, often but not exclusively through effects on glutamate cysteine ligase, the rate-limiting enzyme for glutathione biosynthesis. This upregulation in glutathione provides protection from more severe stress and may be a critical feature of preconditioning and tolerance. In contrast, during aging, glutathione levels appear to decline in a number of tissues, thereby putting cells at increased risk of succumbing to stress. The evidence for such a decline is strongest in the brain where glutathione loss is implicated in both Parkinson's disease and in neuronal injury following stroke.