Prostate cancer is a clinically significant health care problem in the United States. Total prostate specific antigen (tPSA) is widely used to detect prostate cancer with a significant increase in the incidence of organ-confined disease at the time of diagnosis. The limitations of tPSA are low specificity and positive predictive value. Numerous attempts to enhance PSA's performance based on prostate volume, patient age, patient race, and PSA velocity have shown little clinical improvement. Percent free PSA has proven to be somewhat improved but still limited. Recently, the complexed PSA (cPSA) assay was developed and multisite institutional studies have shown that cPSA has improved specificity over tPSA. Complexed PSA can replace tPSA as a first screening test.