Studies from this and other laboratories have shown that the Na-K-2Cl cotransporter is present in BBB endothelial cells is stimulated by factors present during cerebral ischemia. Further, our in situ studies have shown that the cotransporter resides predominantly in the luminal BBB membrane. This is consistent with the hypothesis that a luminal cotransporter works with abluminal Na/K ATPase to secrete NaCl into the brain, and during stroke, BBB cotransporter activity is increased such that the barrier hypersecretes NaCl and water into the brain, facilitating cytotoxic edema formation. Our in vivo MCAO stroke studies provide further support for a role of the BBB cotransporter in cerebral ede-ma formation. Collectively, these findings suggest that the BBB Na-K-2Cl cotransporter does indeed substantially contribute to cerebral edema formation in stroke.