The authors have analyzed the most recent additions to the literature of immunohistochemical and molecular assessment of acquired urethral strictures and report on their data obtained in a selected clinical series. Innovative immunohistochemical studies in patients presenting with plurirecurrent symptoms suggest that urethral mesenchymal changes caused by tissue de-epithelialization may be the underlying cause of stricture. This condition may be congenital or acquired. It may determine aberrant connective tissue formation induced by abnormal fibroblastic activation with formation of over abundant hyperdense collagen scar tissue.