Prostate-specific antigen is the most important, accurate, and clinically useful biochemical marker in the prostate. It is manufactured by the secretory epithelial cells and drains into the ductal system, where it catalyzes the liquefaction of the seminal coagulum after ejaculation. Serum levels are normally less than 4 ng/mL (monoclonal) but vary according to patient age and race; any process that disrupts the normal architecture of the prostate allows diffusion of prostate-specific antigen into the stroma and microvasculature. Elevated serum prostate-specific antigen levels are seen with prostatitis, infarcts, hyperplasia, and transiently after biopsy, but the most clinically important increases are seen with prostatic adenocarcinoma. Cancer produces less prostate-specific antigen per cell than benign epithelium, but the greater number of malignant cells and the stromal disruption associated with cancer account for the increased serum prostate-specific antigen level. Serum prostate-specific antigen level correlates positively with clinical stage, tumor volume, histologic grade, and the presence of capsular perforation and seminal vesicle invasion; despite these strong correlations, its value is limited in predicting stage for individual patients. It may also predict the presence of lymph node metastases, bone metastases, and survival after androgen-deprivation therapy. The use of prostate-specific antigen has resulted in an increase in the early detection rate of cancer, and it is now advocated for annual routine use in men older than 40 years who are at increased risk and in all men older than 50 years. It is a test with high sensitivity and specificity that is rapid, inexpensive, minimally invasive, and acceptable to patients. In addition to serum prostate-specific antigen level, five derivatives of serum prostate-specific antigen were recently described that may increase the predictive value by accounting for confounding variables such as patient age, prostate volume, and cancer volume: age-specific reference ranges, prostate-specific antigen density, prostate-specific antigen velocity, prostate-specific antigen cancer density, and prostate-specific antigen doubling times. Serum prostate-specific antigen detects a heterogeneous group of cancers (clinical stage T1c) that are clinically important and potentially curable. Immunohistochemical expression of prostate-specific antigen in tissue sections allows determination of the prostatic origin of some metastatic adenocarcinomas, although extraprostatic expression of prostate-specific antigen has been reported in several tissues and tumors, including periurethral gland adenocarcinoma in women, rectal carcinoid, and extramammary Paget disease.(ABSTRACT TRUNCATED AT 400 WORDS)