In many disease states, the use of biomarkers is a standard method of determining both the presence and the risk of the future development of disease. For several years, total prostate-specific antigen (PSA) levels have been the standard measure for the diagnosis of prostate cancer (PCa) and other prostatic diseases. However, recent data have indicated that PSA can also be used to determine the risk of developing PCa in the future. This evolving use of PSA is supported by clinical trial data from the Baltimore Longitudinal Study of Aging, the European Randomized Study of Screening for Prostate Cancer, and the Malmö Preventive Medicine Study. Data from the European Randomized Study of Screening for Prostate Cancer have demonstrated that men with a PSA level of > or =1.5 ng/mL are at a significantly elevated risk of developing PCa compared with patients with a PSA level <1.5 ng/mL. The Malmö study showed that the PSA level could independently the predict cancer risk as far as 25-30 years into the future. Secondary nonserum risk factors (eg, age, family history, ethnicity) can also offer predictive value for determining the risk of developing future disease. Furthermore, recent investigations of novel biomarkers have yielded promising PCa prognostic candidates, including the PCa gene 3 and early PCa antigen 2. However, PSA remains the most reliable measure in assessing the risk of developing PCa.