Prostate cancer is the most commonly diagnosed non-skin cancer in men in most western countries. Despite the high morbidity and mortality from prostate cancer, its etiology remains obscure. Although compelling laboratory data suggest a role for androgens in prostate carcinogenesis, most epidemiologic data on humans are inconclusive. To provide insights and directions for future epidemiologic research on hormones and prostate cancer, this review focuses on current perspectives of serum-based studies and polymorphisms in relevant hormone-related genes. We highlight the importance of methodologic studies and investigations of hormone levels in the prostatic tissue to help clarify the often-contradictory data on serologic studies. We recommend careful analysis and cautious interpretation of studies of genetic markers, including repeats and single nucleotide polymorphisms (SNPs), as false positive and negative results may arise in many current and future studies with limited statistical power and non-representative samples from the population. The review also highlights the reasons to perform functional analyses of SNPs, a critical and often under-appreciated component of molecular epidemiologic investigations. The time is ripe for large-scale multidisciplinary investigations that incorporate molecular genetics, biochemistry, histopathology, and endocrinology into traditional epidemiologic studies. Such collaboration will lead to a deeper understanding of the etiologic pathways of prostate cancer, ultimately yielding better preventive, diagnostic, and therapeutic strategies.