Prostate-specific antigen (PSA) is a serine protease member of the human glandular kallikrein family, that is produced by the prostate epithelium and epithelial lining of the periurethral glands. Although considered prostate-specific, PSA has also been detected in breast tissue, breast tumors, endometrium, adrenal neoplasms, and renal cell carcinomas. Low expression of PSA has been reported in other normal or tumor tissues such as urethral, periurethral, and perianal glands, salivary duct carcinoma, and rare mammary carcinomas. Anti-PSA can be used for differentiating high-grade prostate adenocarcinoma from high-grade urothelial carcinoma, as well as for determining the prostatic origin of carcinomas in non-prostate tissues. Anti-PSA recognizes primary and metastatic prostatic neoplasms, but not tumors of nonprostatic origin, and can be useful as an aid to confirm prostatic acinar cell origin in primary and metastatic carcinomas.