Prostate cancer is the most prevalent malignancy in men and the third leading cause of cancer deaths worldwide. Although the wide-spread introduction of total prostate-specific antigen (tPSA) testing has revolutionized the approach to the managed care of this disease, there are some biological, analytical, clinical, and economical issues that argue against the cost-effectiveness of tPSA-based population screening for early identification of cancer. The on-going standardization/harmonization efforts, along with the outcomes of recent epidemiological investigations, demonstrate that the current tPSA thresholds might be revised and possibly recalculated according to several demographical variables, such as age, ethnicity, genotype, family history, and body mass index. A major shortcoming of tPSA screening is the lack of reliable evidences of reduction in prostate cancer-associated mortality, due to the large lead-time because of the indolent growth rate, the impossibility to differentiate high-grade from indolent cancers, and the treatment-associated morbidity. Since no single tPSA cut-off was proven able to efficiently identify men at higher risk of death, the jeopardy of over-diagnosis and over-treatment is also tangible. The large expenditure is an additional source of concern. Finally, a wide-spread population screening also carries several ethical, social, and psychological implications, which might overwhelm the potential benefits.