- The mechanisms underlying the development and progression of psychiatric illnesses are only partially known. Clinical data suggest blood-brain barrier (BBB) breakdown and inflammation are involved in some patients groups. Here we put forward the “BBB hypothesis” and abnormal blood-brain communication as key mechanisms leading to neuronal dysfunction underlying disturbed cognition, mood, and behavior. Based on accumulating clinical data and animal experiments, we propose that events within the “neurovascular unit” are initiated by a focal BBB breakdown, and are associated with dysfunction of brain astrocytes, a local inflammatory response, pathological synaptic plasticity, and increased network connectivity. Our hypothesis should be validated in animal models of psychiatric diseases and BBB breakdown. Recently developed imaging approaches open the opportunity to challenge our hypothesis in patients. We propose that molecular mechanisms controlling BBB permeability, astrocytic functions, and inflammation may become novel targets for the prevention and treatment of psychiatric disorders.