BACKGROUND The widespread use of prostate-specific antigen (PSA) screening has had a tremendous impact on all aspects of the management of prostate carcinoma. Although PSA-based screening has resulted in a stage migration to more organ-confined tumors at the time of diagnosis, and has been temporally associated with a decrease in prostate carcinoma mortality, PSA screening is imperfect. A recent analysis of results from the Prostate Cancer Prevention Trial (PCPT) has provided insight into the positive predictive value of PSA in the so-called "normal" range. METHODS The history of the discovery, initial studies, and subsequent widespread application of PSA screening is reviewed. RESULTS The application of PSA for screening preceded the development of current prostate biopsy techniques and an upper limit of normal was established without complete disease ascertainment. More recent modifications of PSA-based screening have been adopted clinically without sufficient validation. With current methods, overdiagnosis of clinically unimportant disease almost certainly occurs and high-grade, aggressive disease may not be detected sufficiently early to allow successful treatment. CONCLUSIONS To the authors' knowledge, the optimal upper limit of normal for PSA for prostate carcinoma screening is unknown. New biomarkers of disease are needed; these must be linked with disease prognosis and must be validated in rigorously designed clinical trials.