The blood-brain barrier (BBB) is a dynamic interface between the peripheral blood supply and the cerebral parenchyma, controlling the transport of material to and from the brain. Tight junctions between the endothelial cells of the cerebral microvasculature limit the passage of large, negatively charged molecules via paracellular diffusion whereas transcellular transportation across the endothelial cell is controlled by a number of mechanisms including transporter proteins, endocytosis, and diffusion. Here, we review the evidence that perturbation of these processes may underlie the development of psychiatric disorders including schizophrenia, autism spectrum disorder (ASD), and affective disorders. Increased permeability of the BBB appears to be a common factor in these disorders, leading to increased infiltration of peripheral material into the brain culminating in neuroinflammation and oxidative stress. However, although there is no common mechanism underpinning BBB dysfunction even within each particular disorder, the tight junction protein claudin-5 may be a clinically relevant target given that both clinical and pre-clinical research has linked it to schizophrenia, ASD, and depression. Additionally, we discuss the clinical significance of the BBB in diagnosis (genetic markers, dynamic contrast-enhanced-magnetic resonance imaging, and blood biomarkers) and in treatment (drug delivery).