Prostate cancer is the most common non-skin cancer among men in most Western populations and is the second leading cause of cancer death in the United States. Despite its high morbidity, the etiology of prostate cancer remains largely unknown. Age, race, and family history are the only established risk factors. Many other factors, including hormones, diet, physical activity, sexual factors, inflammation, and obesity, have been implicated but their roles are unclear. Genetic influences may account for up to 42% of the risk of prostate cancer, involving both rare, highly penetrant genes and more common, weakly penetrant genes. The pathogenesis of prostate cancer likely involves a complex interplay between environmental and genetic factors. Large, well-designed, interdisciplinary epidemiologic studies are needed to unravel these complex relationships. With newly available molecular tools, a new generation of large-scale, multidisciplinary population-based studies is beginning to investigate gene-gene and gene-environment interactions, which may lead to better detection, treatment, and prevention of prostate cancer.Prostate cancer is the most common non-skin cancer among men in most Western populations and is the second leading cause of cancer death in the United States. Despite its high morbidity, the etiology of prostate cancer remains largely unknown. Age, race, and family history are the only established risk factors. Many other factors, including hormones, diet, physical activity, sexual factors, inflammation, and obesity, have been implicated but their roles are unclear. Genetic influences may account for up to 42% of the risk of prostate cancer, involving both rare, highly penetrant genes and more common, weakly penetrant genes. The pathogenesis of prostate cancer likely involves a complex interplay between environmental and genetic factors. Large, well-designed, interdisciplinary epidemiologic studies are needed to unravel these complex relationships. With newly available molecular tools, a new generation of large-scale, multidisciplinary population-based studies is beginning to investigate gene-gene and gene-environment interactions, which may lead to better detection, treatment, and prevention of prostate cancer.