The blood-brain barrier (BBB) is a multicellular structure that separates the central nervous system (CNS) from the peripheral blood circulation, maintaining brain homeostasis, regulating transport, and protecting against harmful substances. The BBB is composed of endothelial cells (ECs) with tight junctions, pericytes, astrocytes, and the extracellular matrix (ECM). Recent studies have revealed the importance of various signaling pathways and cell types in the development and maintenance of the BBB. Key regulators include VEGF, Wnt, Hedgehog, and GPR124, which influence angiogenesis, barrier formation, and immune cell trafficking. Disruption of the BBB can lead to neuroinflammation and neurodegeneration, as seen in conditions like ischemic stroke, epilepsy, and ALS. Therapeutic approaches to repair the BBB include glucocorticosteroids and mesenchymal stromal cells (MSCs), but more selective treatments are needed. The BBB's role in disease and its potential for repair are areas of ongoing research, with new model systems and in vitro methods enhancing our understanding of this complex barrier.The blood-brain barrier (BBB) is a multicellular structure that separates the central nervous system (CNS) from the peripheral blood circulation, maintaining brain homeostasis, regulating transport, and protecting against harmful substances. The BBB is composed of endothelial cells (ECs) with tight junctions, pericytes, astrocytes, and the extracellular matrix (ECM). Recent studies have revealed the importance of various signaling pathways and cell types in the development and maintenance of the BBB. Key regulators include VEGF, Wnt, Hedgehog, and GPR124, which influence angiogenesis, barrier formation, and immune cell trafficking. Disruption of the BBB can lead to neuroinflammation and neurodegeneration, as seen in conditions like ischemic stroke, epilepsy, and ALS. Therapeutic approaches to repair the BBB include glucocorticosteroids and mesenchymal stromal cells (MSCs), but more selective treatments are needed. The BBB's role in disease and its potential for repair are areas of ongoing research, with new model systems and in vitro methods enhancing our understanding of this complex barrier.