Increased oxidative stress and chronic inflammation are involved in the initiation and progression of most chronic diseases. Based on the results of animal studies in which a single antioxidant reduced the risk of developing chronic diseases, well-designed clinical studies primarily using a single dietary antioxidant in high-risk populations, such as cancer, coronary artery disease (CAD), Alzheimer’s disease (AD), and Parkinson’s disease (PD) were performed. The results of these studies varied from no effects, transient beneficial effects, to harmful effects. The scientific reasons for these varied results with single antioxidants were presented, and a shift in experimental design from using one antioxidant alone to multiple micronutrients was suggested. In order to simultaneously reduce oxidative stress and chronic inflammation, it is necessary to elevate the levels of antioxidant enzymes through the activation of Nrf2/ARE pathway, and dietary and endogenous antioxidants. A micronutrient mixture that would achieve the above goal was proposed. Modifications in diet and lifestyle were also suggested. The recommended micronutrient mixture together with changes in diet and lifestyle should be tested in high-risk populations of chronic diseases by well-designed randomized, double-blind, placebo-controlled trials.