An urgent need exists to develop a more sophisticated screening system in order to improve diagnostic accuracy of clinically significant cancer and also to reduce the drawbacks of prostate-specific antigen (PSA) screening including overdetection and overtreatment. The most promising next-generation PSA test, which can improve the management of prostate cancer, may be proenzyme PSA (proPSA) or precursor PSA (pPSA). proPSA has pro-leader peptide sequences of seven or less amino acids and previous studies demonstrated that [-2]proPSA, which contains only a 2-amino-acid propeptide leader, could be more useful not only to distinguish between men with and without cancer, but also between tumors with aggressive features with performance exceeding other classical PSA-related indices including ratio of free PSA to total PSA (%f-PSA) and PSA density. Recently, it was demonstrated that baseline [-2]proPSA-related indices were independent factors to predict pathological reclassification at one year or several years after entering active surveillance. Furthermore, a retrospective study suggested that [-2]proPSA might be a useful predictive marker for future developing clinically manifested prostate cancer as well as aggressive tumors. ProPSA-related indices may have the potential for developing a more ideal risk classification for men at risk for prostate cancer, with a screening system maintaining the sensitivity of detecting clinically significant prostate cancer while saving cost, individualized treatment strategies, and follow-up procedures of active surveillance or active treatments. At a minimum, proPSA will be one of the most important new markers on the prostate cancer management in the near future.