P-glycoprotein (Pgp), a multidrug resistance (mdr) protein, is expressed by endothelial cells at blood–brain and other blood–tissue barrier sites. This expression was detected using mouse monoclonal antibodies against the human mdr1 gene product. The presence of Pgp in these endothelial cells suggests a physiological role in regulating the entry of certain molecules into the central nervous system and other anatomic compartments, such as the testes. These tissues, which limit the access of systemic drugs, are known pharmacologic sanctuaries for metastatic cancer. The expression of Pgp in capillary endothelium of the brain and testes, but not in other tissues like the kidney and placenta, may explain this phenomenon and has important implications for cancer chemotherapy. The failure of chemotherapy to eradicate all cancer cells may be due to drug resistance, which is associated with the overexpression of Pgp. Pgp is believed to function as an energy-dependent drug efflux pump, contributing to multidrug resistance. Pgp has been reported in various human tumors and normal tissues, including specialized epithelial cells and trophoblasts in the placenta. However, the most intriguing finding is the strong expression of Pgp in endothelial cells of capillary blood vessels at blood–tissue barrier sites, including the central nervous system, testes, and papillary dermis. The expression of Pgp in these endothelial cells may play a role in limiting the entry of certain molecules into the brain and testes, which are known pharmacologic sanctuaries. This could explain why some cancer cells survive chemotherapy in these areas. The identification of Pgp in these endothelial cells raises the possibility that this protein is an operative component of these systems. The blood–brain barrier, characterized by tight junctions between endothelial cells, limits the passage of certain molecules into the brain. Pgp expression in the brain and testes may contribute to this barrier function. The expression of Pgp in the papillary dermis may also be related to the protection of the epidermis from toxic substances. The presence of Pgp in these endothelial cells suggests a physiological role in regulating the entry of certain molecules into specific anatomic compartments. This function may explain the failure of systemic chemotherapy to eradicate otherwise drug-sensitive tumor cells in known pharmacologic sanctuaries such as the brain and testis. Understanding the role of Pgp in these barriers is important for developing therapeutic strategies to overcome drug resistance and improve the efficacy of chemotherapy.P-glycoprotein (Pgp), a multidrug resistance (mdr) protein, is expressed by endothelial cells at blood–brain and other blood–tissue barrier sites. This expression was detected using mouse monoclonal antibodies against the human mdr1 gene product. The presence of Pgp in these endothelial cells suggests a physiological role in regulating the entry of certain molecules into the central nervous system and other anatomic compartments, such as the testes. These tissues, which limit the access of systemic drugs, are known pharmacologic sanctuaries for metastatic cancer. The expression of Pgp in capillary endothelium of the brain and testes, but not in other tissues like the kidney and placenta, may explain this phenomenon and has important implications for cancer chemotherapy. The failure of chemotherapy to eradicate all cancer cells may be due to drug resistance, which is associated with the overexpression of Pgp. Pgp is believed to function as an energy-dependent drug efflux pump, contributing to multidrug resistance. Pgp has been reported in various human tumors and normal tissues, including specialized epithelial cells and trophoblasts in the placenta. However, the most intriguing finding is the strong expression of Pgp in endothelial cells of capillary blood vessels at blood–tissue barrier sites, including the central nervous system, testes, and papillary dermis. The expression of Pgp in these endothelial cells may play a role in limiting the entry of certain molecules into the brain and testes, which are known pharmacologic sanctuaries. This could explain why some cancer cells survive chemotherapy in these areas. The identification of Pgp in these endothelial cells raises the possibility that this protein is an operative component of these systems. The blood–brain barrier, characterized by tight junctions between endothelial cells, limits the passage of certain molecules into the brain. Pgp expression in the brain and testes may contribute to this barrier function. The expression of Pgp in the papillary dermis may also be related to the protection of the epidermis from toxic substances. The presence of Pgp in these endothelial cells suggests a physiological role in regulating the entry of certain molecules into specific anatomic compartments. This function may explain the failure of systemic chemotherapy to eradicate otherwise drug-sensitive tumor cells in known pharmacologic sanctuaries such as the brain and testis. Understanding the role of Pgp in these barriers is important for developing therapeutic strategies to overcome drug resistance and improve the efficacy of chemotherapy.