Over the past three decades, progress in radiotracer chemistry and instrumentation for positron emission tomography (PET) has enabled us to test mechanistic hypotheses of psychiatric illness generated by integrating clinical observations, animal models, and postmortem data. A major advance in the early 1990s was the development and validation of PET methods to directly measure changes in endogenous dopamine (1, 2). Initially, serial PET scans with radiotracers for the dopamine (D2/3) receptor were performed after administration of a placebo or drugs that increased (e.g., d-amphetamine, methylphenidate) or decreased (e.g., reserpine, alpha-methyl-para-tyrosine) dopamine concentrations. The majority of studies were performed with the substituted benzamide class of radiotracers: [11C]raclopride for PET. In fact, raclopride was developed originally as an antipsychotic drug. These antagonist radiotracers bind to the D2/3 receptor and compete with dopamine so that a pharmacologic increase in endogenous dopamine concentrations would produce a decrease in [11C]raclopride binding; or vice versa, a decrease in dopamine would increase [11C]raclopride binding. For the first time, the role of dopamine in many psychiatric and neurological conditions could be evaluated in vivo, and the variability in response could be interpreted in the context of behaviors or symptoms, such as craving, attention, impulsivity, and psychosis, of treatment response, and of genetic polymorphisms related to dopamine neurotransmission (3–7). The method was also used to study neurotransmitter interactions in vivo by investigating the effect of drugs that affect serotoninergic, cholinergic, and glutamatergic systems (N-methyl-d-aspartic acid receptor antagonist, ketamine) on dopamine concentrations (8, 9). Importantly, the method has been used to study changes in endogenous dopamine during performance of cognitive tasks, induction of behavioral states, or brain stimulation (10–12). Dopamine agonist radiotracers that image receptors in the high affinity state have also been evaluated and, as expected, show greater sensitivity to changes in dopamine concentrations than the dopamine antagonist tracers (13). The applications of these methods seemed endless and the results very intriguing, but we were left with a major limitation: we could only measure changes in the basal ganglia where dopamine D2/3 receptor concentrations are high. It was not possible to visualize cortical and limbic regions that are involved in cognition and emotion because of the relatively low concentration and relatively rapid radiotracer washout of cortical D2/3 receptors.