A large body of observational epidemiologic studies has consistently demonstrated that individuals who eat more fruits and vegetables, which are rich in carotenoids, and people who have higher serum β-carotene levels have a lower risk of cancer, particularly lung cancer. In contrast to these observations, two human intervention studies that used high-dose β-carotene supplements reported an increased risk for lung cancer among smokers. Recently, in vitro and in vivo studies have shed light on the present conundrum regarding the potential chemopreventive activity of β-carotene; that is, β-carotene itself may act as an anticarcinogen, but its oxidized products may facilitate carcinogenesis. These studies support the hypothesis that the carcinogenic response to high-dose β-carotene supplementation reported in the human intervention trials is related to the instability of the β-carotene molecule in the free radical–rich environment in the lungs of cigarette smokers. This is especially possible because smoke also causes decreased tissue levels of other antioxidants, such as ascorbate and α-tocopherol, which normally have a stabilizing effect on the unoxidized form of β-carotene. Nutritional intervention using a combination of antioxidants (β-carotene, α-tocopherol, and vitamin C) as anticarcinogenic agents could be an appropriate way to rationally and realistically reduce cancer risk.