Prostate cancer (PCa) is one of the most common solid cancers and one of the most important causes of morbidity and mortality worldwide in men. So far, several efforts have been devoted to identify prostate cancer biomarkers, which allow a discrimination between indolent and clinically significant diseases, however with scarce results. The prostate-specific antigen (PSA) still remains the marker of choice for PCa diagnosis, prognosis, and «active surveillance». Thus, a sensitive and specific independent indicator, easy to screen in blood or urine is still not available. This review will provide a new insight into the role of previous (i.e. PSA) and new biomarkers, to use separately or in combination for prostate cancer screening and early detection programs.