Glutathione plays a central role in the maintenance of tissue antioxidant defenses and in the regulation of redox sensitive signal transduction. In muscle cells, the level and redox status of GSH regulates activity of the redox sensitive transcription factor NF-kappaB. Physical exercise may cause oxidation of GSH in tissues such as the blood, skeletal muscle and liver. Endurance training strengthened GSH dependent tissue antioxidant defenses in most studies. Although studies investigating the effect of sprint training are few, current results show that sprint training may also have a beneficial effect on tissue GSH homeostasis. Skeletal muscle GSH level appears to be tightly regulated by the state of physical activity. Regular exercise enhances and chronic inactivity decreases the level of GSH in this tissue. N-acetyl-L-cysteine (NAC) and alpha-lipoic acid (LA) are two antioxidant dietary supplements that are able to enhance cellular GSH levels. Because LA can be recycled to its potent dithiol form, dihydrolipoate, by enzymes present in the human cell it has a clear advantage over NAC. Recently an improved form of LA, a positively charged analogue (LA-Plus), has been discovered. LA-Plus has more potent immuno-modulatory activity compared to LA. Both LA and NAC have been shown to have beneficial effects in protecting tissue GSH homeostasis against exercise induced oxidative stress.