Obsessive-compulsive disorder (OCD) has a long history of speculations concerning its cause. This article reviews human functional neuroimaging studies of OCD, then presents data from a study in the nonhuman primate that concerns the localization of brain systems that may mediate the expression of OCD symptoms. We use these lines of evidence to argue that increased "neural tone" through a section of the behaviorally disinhibiting "direct" basal ganglia pathway, relative to tone in the behaviorally inhibiting or moderating "indirect" basal ganglia system, may mediate the expression of OCD symptoms. The limbic orbital prefrontal cortex, the involvement of which is highly implicated in OCD, may have a greater influence on neural tone in the direct pathway than in the indirect, whereas more dorsal neocortical prefrontal regions may have the opposite effects on these two basal ganglia subsystems. Effective OCD treatments may obtain their results by preferentially decreasing neural tone through the direct relative to the indirect basal ganglia system.