Steadily accumulating scientific evidence supports the general importance of oxidative damage of tissue and cellular components as a primary or secondary causative factor in many different human diseases and aging processes. Our goal has been to develop sensitive and reliable means to measure the oxidative damage and defense/repair status of an individual that could be easily used by a physician to determine whether there is an immediate or long-term increased health risk to their patients with regard to oxidative damage. We also sought to try to determine how this risk can best be reduced, and whether the prescribed therapy is working and how it might be best adjusted to optimize benefits. We have found that combining both an oxidative damage profile with a defense/repair profile produces the most reliable set of information to meet these objectives. Success is indicated by demonstrating the expected inverse correlation of oxidative stress vs. antioxidant status of a population of several hundred individuals. We also find support that oxidative stress status is under tight regulatory control for most individuals over a wide range of lifestyle variables including diet and exercise. Indeed only about 10% of the individuals analyzed appear to have unusually high oxidative stress levels. Only these individuals having the higher than normal levels of oxidative stress are the best responders to antioxidant supplements to lower their oxidative stress status to normal levels. We discuss the implications of these results for human application and review how current clinical studies are carried out to evaluate the benefits of antioxidant supplements in reducing the incidence of specific age-dependent disease.