OBJECTIVE The trace element selenium, a constituent of antioxidant enzymes, has been proposed as a chemopreventive agent for prostate and other cancers. METHODS Published epidemiological and scientific studies relating to the potential clinical and molecular role of selenium in preventing cancer are reviewed and summarized. A unifying hypothesis underlying observations on the effect of selenium on early events in carcinogenesis is presented. RESULTS A large body of epidemiological evidence, including observational, case-control, cohort and randomized controlled clinical trials, support the proposition that selenium may prevent prostate cancer in humans. The available data suggest a beneficial effect for men with low baseline serum or toenail selenium levels, without preexisting tumors, with serum prostate specific antigen less than 4 ng/ml and in current or former smokers. Molecular data demonstrate that selenium prevents clonal expansion of nascent tumors by causing cell cycle arrest, promoting apoptosis, and modulating p53 dependent DNA repair mechanisms. CONCLUSIONS These observations give strong scientific support to ongoing clinical trials testing the ability of selenium to prevent prostate cancer and the progression of high grade prostatic intraepithelial neoplasia to cancer.