Encouraged by the potential health benefits of higher dietary intake of substances with beneficial properties, the use of supplements containing these compounds has increased steadily over recent years. The effects of several of these, many of which are antioxidants, have been supported by data obtained in vitro, in animal models, and often by human studies as well. However, as carefully controlled human supplementation trials have been conducted, questions about the efficacy and safety of these supplements have emerged. In this Educational Paper, three different supplements were selected for consideration of the benefits and risks currently associated with their intake. The selected supplements include Ξ²-carotene, selenium, and genistein. The use of each is discussed in the context of preclinical and clinical data that provide evidence for both their use in reducing disease incidence and the possible liabilities that accompany their enhanced consumption. Variables that may influence their impact, such as lifestyle habits, baseline nutritional levels, and genetic makeup are considered and the application of these issues to broader classes of supplements is discussed.