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BACKGROUND Dystroglycan is a cell-surface receptor for extracellular matrix proteins including laminins and perlecan. Prior studies have shown its involvement in assembly and/or maintenance of basement membrane structures, cell polarity and tissue morphogenesis; and its expression is often reduced in prostate and other cancers. However, the role of dystroglycan in normal epithelial tissues such as the prostate is unclear. METHODS To investigate this, we disrupted dystroglycan expression in the prostate via a conditional gene targeting strategy utilizing Cre recombinase expressed in luminal prostate epithelial cells. RESULTS Contrary to expectations, deletion of dystroglycan in luminal epithelial cells resulted in no discernable phenotype as judged by histology, basement membrane ultrastructure, localization of dystroglycan ligands, cell polarity or regenerative capacity of the prostate following castration. Dystroglycan expression remains in keratin-5-positive basal cells located in the proximal ducts where dystroglycan expression is elevated in regenerating prostates. CONCLUSIONS Our results show that dystroglycan in luminal epithelial cells is not required for the maintenance of basement membranes, cell polarity or prostate regeneration. However, it is possible that persistent dystroglycan expression in the basal cell compartment may support these or other functions. Prostate 70: 777–787, 2010. © 2010 Wiley-Liss, Inc.