The central nervous system (CNS) neurovasculature exhibits specialized properties, termed the blood-brain barrier (BBB), which brain homeostasis. The BBB functions not only as a physical barrier to separate the CNS from the periphery through the expression of an elaborate junctional network, but also as an immunological barrier to suppress the expression of pro-inflammatory mediators. Improper BBB functioning can promote neuroinflammation and disease, and multiple neurological disorders have been tied to these phenotypes, including schizophrenia. However, despite ample clinical evidence reporting BBB impairment in schizophrenia, little is known about the causes and consequences of BBB disruption in this disease. Here, we utilize human in vitro, murine in vivo and human post mortem tissue to study the BBB in the 22q11.2 deletion syndrome (22qDS), a condition that confers a 25-fold increased risk for schizophrenia. As the 22q11.2 deletion represents the strongest monogenic risk allele for schizophrenia and includes mitochondrial and junctional genes, we hypothesized that BBB dysfunction may contribute to the increased risk for schizophrenia in this population. We report that the 22qDS BBB demonstrates deficits in barrier function, tight junction expression, immune properties, and mitochondrial function. We demonstrate that mitochondrial dysfunction may contribute to impaired barrier integrity, as treatment to improve mitochondrial respiration enhanced BBB function. We further investigated the consequences of BBB dysfunction, and our finding of perivascular astrocyte activation suggest that BBB impairment may drive neuroinflammation in 22qDS. We demonstrate the behavioral relevance of BBB dysfunction, as we report that improving BBB integrity restores performance in clinically-relevant tasks. Finally, we report that immune challenge, a known risk factor for schizophrenia, causes worsened mitochondrial and barrier phenotypes alongside exacerbated neuroinflammation. Together, the work presented in this thesis demonstrates that genetic susceptibility to neuropsychiatric disease is associated with BBB dysfunction, which may contribute to neuroinflammation and disease.