Three large-scale clinical trials tested the effects of supplemental beta-carotene on the risk for chronic diseases such as cancer. The populations involved were Finnish male heavy smokers (the Alpha Tocopherol Beta Carotene [ATBC] trial), male asbestos workers and male and female heavy smokers (Beta-Carotene and Retinol Efficacy Trial [CARET]), and U.S. male physicians, 11% of whom were current smokers (Physician's Health Study). All three trials concluded that beta-carotene provided no protection against lung cancer; however, quite unexpectedly, two of the trials found a higher risk for lung cancer for those subjects given beta-carotene compared with those that were not. Several authors concluded from these beta-carotene trials that the protective effects of antioxidants against chronic disease are not as great as had been hoped. As reviewed here, however, beta-carotene may or may not be an antioxidant; it certainly differs in many respects from the prototypical antioxidant, vitamin E. In any case, the majority of beta-carotene's effects in vivo are probably not derived from any antioxidant properties that it may possess, but rather from its effect on a number of biochemical systems. Whether taking supplemental antioxidants can reduce the risk for chronic diseases remains to be established, although the case for vitamin E and heart disease appears strong. However, the association between eating a diet sufficient in fruits and vegetables and reduced risk for a number of diseases is consistent. There is no evidence at present that consuming small amounts of supplemental beta-carotene, i.e., amounts in foods or in a multivitamin tablet, is unwise for any population. The role of supplementation, however, particularly at high levels, with compounds that may be anti-oxidants but that are less well understood than vitamin E (e.g., carotenoids, plant polyphenols, and other phytochemicals), is less clear. The surprising results of the ATBC and CARET trials are a red flag, signaling the need for further research; a number of areas for future work are suggested here. Future research should lead to a clearer understanding of the effects of beta-carotene and other phytochemicals, as well as to more refined strategies for intervention, with important clinical and public health implications.