We have shown that mice lacking CD73, an extracellular enzyme of the purine catabolic pathway that catalyzes the breakdown of adenosine monophosphate (AMP) to adenosine, were resistant to EAE, the animal model of the central nervous system (CNS) inflammatory disease multiple sclerosis (MS). Furthermore, blockade of adenosine receptor signaling with an antagonist specific for the A2a adenosine receptor, which is expressed in the CNS, inhibited lymphocyte migration into the CNS and protected wild type mice from EAE. We now show that blockade of adenosine receptors with broad spectrum or a specific A2a receptor antagonist prohibits the entry of immune cells into the CNS of (SJL/J x PL/J)F1 mice (that develop a relapsing-remitting form of EAE), inhibits the development of EAE, and halts EAE relapse. Importantly, we have strong data showing that adenosine receptor blockade can inhibit the entry of molecules such as FITC-Dextran and Evans blue dye across CNS barriers. These data provide convincing evidence that modulation of adenosine receptors can have a profound effect on CNS mediated diseases such as MS and drug delivery across CNS barriers. This work was supported by NIH grants AI 57854 and NS 063011 (to MSB) and AI 18220 (to LFT).