The blood-CSF barrier (BCSFB) in choroid plexus works with the blood-brain barrier (BBB) in cerebral capillaries to stabilize the fluid environment of neurons. Dysfunction of either transport interface, i.e., BCSFB or BBB, causes augmented fluxes of ions, water and proteins into the CNS. These barrier disruptions lead to problems with edema and other compromised homeostatic mechanisms. Hyperthermic effects on BCSFB permeability and transport are not as well known as for BBB. However, it is becoming increasingly appreciated that elevated prostaglandin synthesis from fever/heat activation of cyclooxygenases (COXs) in the BCSFB promotes water and ion transfer from plasma to the ventricles; this harmful fluid movement into the CSF-brain interior can be attenuated by agents that inhibit the COXs. Moreover, new functional data from our laboratory animal model indicate that the BCSFB (choroidal epithelium) and the CSF-bordering ependymal cells are vulnerable to whole body hyperthermia (WBH). This is evidenced from the fact that rats subjected to 4h of heat stress (38 degrees C) showed a significant increase in the translocation of Evans blue and (131)Iodine from plasma to cisternal CSF, and manifested blue staining of the dorsal surface of the hippocampus and caudate nucleus. Degeneration of choroidal epithelial cells and underlying ependyma, a dilated ventricular space and damage to the underlying neuropil were frequent. A disrupted BCSFB is associated with a marked increase in edema formation in the hippocampus, caudate nucleus, thalamus and hypothalamus. Taken together, these findings suggest that the breaching of the BCSFB in hyperthermia significantly contributes to cell and tissue injuries in the CNS.