This review discusses the results of randomized clinical trials of supplemental micronutrients for cancer prevention completed over the past 20 years, including trials of beta-carotene and retinol, vitamins C and E, selenium, folic acid, and vitamin D. Some trials observed significant reductions in risk, whereas others observed significant increases in risk of the primary cancer endpoint. In considering these trials, it appears that supplementation targeted to populations with low status of the nutrient of interest may prevent cancer, whereas supplementation in populations with higher status or to achieve pharmacological exposures may promote cancer. Observational epidemiologic evidence coupled with these trial results supports the concept of a U-shaped curve for micronutrients in relation to cancer prevention. Based on these data, nutrient supplements are not currently recommended for cancer prevention in the general population. The hypothesis that groups with low nutrient status may benefit from supplementation has yet to be formally tested.