Functional imaging studies have reported with remarkable consistency hyperactivity in the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), and caudate nucleus of patients with obsessive–compulsive disorder (OCD). These findings have often been interpreted as evidence that abnormalities in cortico–basal ganglia–thalamo–cortical loops involving the OFC and ACC are causally related to OCD. This interpretation remains controversial, however, because such hyperactivity may represent either a cause or a consequence of the symptoms. This article analyzes the evidence for a causal role of these loops in producing OCD in children and adults. The article first reviews the strong evidence for anatomical abnormalities in these loops in patients with OCD. These findings are not sufficient to establish causality, however, because anatomical alterations may themselves be a consequence rather than a cause of the symptoms. The article then reviews three lines of evidence that, despite their own limitations, permit stronger causal inferences: the development of OCD following brain injury, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection, and neurosurgical lesions that attenuate OCD. Converging evidence from these various lines of research supports a causal role for the cortico–basal ganglia–thalamo–cortical loops that involve the OFC and ACC in the pathogenesis of OCD in children and adults.