Recent studies have cast doubt on the reliability of serum total prostate-specific antigen as a biomarker for the detection and prognosis of prostate cancer. Biomarkers that can identify those men at risk for clinically significant prostate cancer are desperately needed. The search for biomarkers that may improve the detection of biologically consequential prostate cancer is one of the most active areas under current investigation. In this review, we highlight some of these ongoing efforts. Proper validation of newly discovered biomarkers is of paramount importance.