Protection against free radical-initiated oxidative damage has long been recognized as the most important function of vitamin E. However, the mechanism by which vitamin E exerts its antioxidant function in vivo has yet to be delineated. Available information suggests that vitamin E may exert its antioxidant function at the tissue level by mediating the levels or generation of mitochondrial superoxide. Mitochondrion is the major source of superoxide, and high concentration of vitamin E is found in the inner membrane. Superoxide is a key precursor for such biologically important reactive oxygen species as hydrogen peroxide and peroxynitrite, and is capable of releasing iron from its protein complexes. The labile or free form of iron, in turn, can catalyze the formation of hydroxyl radicals from hydrogen peroxide. Both hydroxyl radicals and peroxynitrite have potential to initiate oxidative damage to essential biomembranes, proteins and DNA. Recently dietary vitamin E has been shown to reduce the levels/generation of mitochondrial superoxide, and to attenuate the tissue levels of labile iron. By reducing available superoxide, dietary vitamin E may decrease the generation of hydroxyl radicals and peroxynitrite, and thus attenuate oxidative damage. Also, by altering the levels/generation of reactive oxygen species, vitamin E may modulate the activation and/or expression of important redox-sensitive biological modifiers that mediate vital cellular events.