Deficiencies of selenium have been associated with an increased cancer risk, and several clinical and animal trials have suggested that improved selenium nutrition may reduce the incidence of several kinds of cancer, including lung, colorectal, and breast. Results from recent trials also show an anticarcinogenic effect of selenium in the prostate. There is converging evidence from epidemiologic, experimental animal, and molecular biology studies for an antitumor effect of selenium. Evidence suggests there are two modes of action of selenium affecting cancer risk: first, by functioning as an essential nutrient that provides the catalytic centers of a number of selenoenzymes, including some with antioxidant and redox functions; second, by serving as a source of selenium metabolytes that affect carcinogenesis in other ways. The first mechanism appears most relevant to protection against cancer initiation, the second against cancer progression. There is conclusive evidence of the increased risk of prostate cancer for a male with a family history of the disease. As a result of this evidence, and the evidence supporting the chemopreventive properties of selenium, this study proposed that a trial to test the effect of selenium on men at high risk for development of prostate cancer is appropriate. This article describes the Australian Prostate Cancer Prevention Trial Using Selenium (APPOSE) trial to test the hypothesis that daily dietary supplementation with selenium will reduce prostate cancer incidence in a population of men who are at increased risk because of a first-degree relative with prostate cancer.