Tight junctions (TJs) of the cerebral endothelial cells play a crucial role in the regulation of BBB permeability under physiological, as well as pathological conditions. The regulation of the junctional proteins is under a complex control. In these regulatory processes signalling molecules, some of them localized to the TJ, play an important role. Among the best characterized second messengers which regulate TJ function are the cyclic nucleotides, which, as shown in our experiments, as well, decrease paracellular permeability. Another important signalling molecule involved in TJ regulation is protein kinase C, which may affect differently the formation of TJ and the function of mature TJ. Further signalling molecules known to regulate paracellular permeability are G-proteins, both conventional and small G-proteins, MAP kinases and other protein kinases. Much of our knowledge concerning second messenger regulation of TJ arises fon the study of epithelial cells of different origin, mostly from kidney, therefore the specific regulation of the junctional complex of the BBB still remains to be elucidated.