Oxidative stress over time leads to the accumulation of damaged macromolecules and to profound physiological changes that are associated with several age-related diseases. The plasma membrane redox system (PMRS) appears to attenuate oxidative stress acting as a compensatory mechanism during the aging process. The PMRS appears to play a protective role during mitochondrial dysfunction to provide cells with a survival mechanism by lowering oxidative stress. The PMRS accomplishes this by producing more NAD(+) for glycolytic ATP production via transfer of electrons from intracellular reducing equivalents to extracelluar acceptors. Ubiquinone and alpha-tocopherol are key antioxidant molecules in the plasma membrane that are affected by aging and can be up-regulated by dietary interventions such as calorie restriction (CR). Up-regulation of PMRS activity leads to cell survival and membrane homeostasis under stress conditions and during calorie restriction. Further studies of the PMRS may provide not only additional information on the mechanisms involved in aging and CR, but may provide therapeutic targets for the prevention and treatment of age-related diseases.