The blood-brain barrier (BBB) is partially composed of specific endothelial cells and protects the central nervous system (CNS) from pathogens and large molecules circulating in the blood. Alexandre Prat and colleagues now report that the Hedgehog signaling pathway promotes BBB formation by modulating the anti-inflammatory system (Science, published online 1 December 2011; doi:10.1126/science.1206936). The authors observed that Sonic hedgehog (Shh) was present in astrocyte-conditioned medium (ACM) but was not in endothelial cells or pericytes. They found that human Shh increased transendothelial electrical resistance (TEER) in human BBB endothelial cells and decreased permeability to large molecules. Treating these cells with cyclopamine, which antagonizes the Hedgehog pathway effector Smoothened (Smo), reversed the effects of ACM-conditioned medium. In addition, injecting mice with cyclopamine led to breakdown of the BBB in vivo. The authors constructed a conditional knockout allele that specifically removed Smo function in endothelial cells, which led to significant increases in BBB permeability. Hedgehog activation promoted quiescence of the immune system by lowering the levels of proinflammatory mediators, and the authors suggest that these new insights may lead to improvements in the delivery of drugs and therapeutics into the CNS.