Glutathione (GSH) is the main antioxidant in the body and conjugates and eliminates a variety of toxicants, reactive oxygen species, and heavy metals. Clinical and experimental evidence has accumulated that females in humans and other mammals have higher glutathione levels than males. Understanding how hepatic GSH levels depend on estradiol is important since oxidative stress contributes to certain diseases, and oxidative stress is reduced by GSH. We use mathematical modeling to explore the causes and consequences of sex differences in GSH levels, including the stability of GSH during the menstrual cycle and variations in one-carbon metabolism in pre- and post-menopausal women undergoing hormone supplementation.