The three beta-carotene intervention trials: the Beta Carotene and Retinol Efficacy Trial (CARET), Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC), and Physician's Health Study (PHS) have all pointed to a lack of effect of synthetic beta-carotene in decreasing cardiovascular disease or cancer risk in well-nourished populations. The potential contribution of beta-carotene supplementation to increased risk of lung cancer in smokers has been raised as a significant concern. The safety of synthetic beta-carotene supplements and the role of isomeric forms of beta-carotene (synthetic all-trans versus "natural" cis-trans isomeric mixtures), in addition to the importance of the protective role of other carotenoids like lycopene and lutein, have become topics of debate in the scientific and medical communities. This review addresses the biochemistry and physiology of the cis versus trans isomers of beta-carotene as well as relevant studies comparing the absorption and storage of the synthetic versus natural forms of beta-carotene. In addition, the risk of potential pro-oxidant effects of synthetic beta-carotene supplementation in intervention trials is evaluated.