The purpose of this article is to review the available means to investigate whether an elevated serum prostate-specific antigen (PSA) after radical prostatectomy may be explained by the presence of residual benign tissue. To answer this question, one may consider the following features: the kinetics of recurrent/ persistent PSA, the incidence of rising PSA in the presence of capsular incisions exposing benign glands only, the level of urinary PSA and the ratio of free/total PSA in the urine, the results of anastomotic biopsy samples, and the detection of circulating prostate cells by PSA reverse transcriptase-polymerase chain reaction (RT-PCR) after surgery. Capsular incisions exposing benign tissue are not associated with a significant risk of biochemical failure. In case of an organ-confined cancer with negative surgical margins but a rising postoperative PSA, the systematic reevaluation of the initial pathological slides constantly shows capsular effraction or focal positive margins that have been overlooked at the first evaluation. Even when anastomotic biopsies document only benign tissue, the study of PSA doubling time is usually characteristic of the coexistence of residual tumoral cells. However, in a few cases, the persistent negative results of the detection of circulating prostate cells by PSA, RT-PCR in patients with organ-confined cancer and negative margins but elevated postoperative PSA might be explained by the presence of residual benign prostatic hyperplasia tissue. Most of the data in the literature are in favor of the responsibility of persistent/recurrent cancer in the recurring PSA rather than that of benign prostatic hyperplasia/normal residual tissue. Therefore, a persistent/recurrent detectable level of PSA is the serum after radical prostatectomy characterizes biochemical failure.