Brain microvasculature constitute a highly specialized and selective vascular barrier between blood and the central nervous system, called blood brain barrier (BBB). In these vessels endothelial cells present a highly developed system of tight junctions (TJs), absence of fenestration and low pinocytotic activity. Cells of the brain parenchyma, the astrocytes, contribute to the BBB-coverage with their foot processes, which constitute about the eighty percent of the basal aspect of the vessels. As a consequence, circulating solutes do not readily enter the brain parenchyma unless through specific endothelial “transporters”. Thus, BBB also limits the passage of anti-cancer drugs from the blood to the brain. Therefore, it would be therapeutically useful to develop systems to modulate BBB permeability. To this aim it is important to define the molecular mechanisms that regulate the establishment and maintenance of BBB properties. Data from our laboratory suggest a key role of the Wnt/β-catenin signaling pathways in the induction, regulation and maintenance of the BBB characteristics during embryonic and post-natal development. In endothelial cells, Wnt signaling induces barrier differentiation by increasing the stabilization and the transcriptional activity of β-catenin. On the contrary, inactivation of β-catenin causes significant downregulation of junctional proteins, and consequent BBB breakdown. Besides β-catenin, other three proteins, CCM1, CCM2 and CCM3, expressed by brain endothelial cells, are emerging as key modulators of the organization and function of the BBB. Indeed, mutations occurring in any of the genes encoding these proteins, leads to Cerebral Cavernous Malformation (CCM), a pathology characterized by brain vascular malformations. The endothelium in the lesions presents very few tight junctions and gaps are observed between endothelial cells. In addition, the vascular basal lamina is disorganized and the astrocytes do not take contact with the endothelial wall. The structural alterations of the BBB observed in CCM lesions are associated with severe clinical manifestations, such as cerebral haemorrhages and stroke. Additional data point to a possible link between inflammatory cytokines and the function of CCM proteins in the regulation of BBB stability. These data open new therapeutic opportunities for this so far incurable disease