||The drug treatment of Parkinson’s disease (PD) is accompanied by a loss of drug efficacy, the onset of motor complications, lack of effect on non-motor symptoms, and a failure to modify disease progression. As a consequence, novel approaches to therapy are sought, and adenosine A2A receptors (A2AARs) provide a viable target. A2AARs are highly localized to the basal ganglia and specifically to the indirect output pathway, which is highly important in the control of voluntary movement. A2AAR antagonists can modulate γ-aminobutyric acid (GABA) and glutamate release in basal ganglia and other key neurotransmitters that modulate motor activity. In both rodent and primate models of PD, A2AAR antagonists produce alterations in motor behavior, either alone or in combination with dopaminergic drugs, which suggest that they will be effective in the symptomatic treatment of PD. In clinical trials, the A2AAR antagonist istradefylline reduces “off” time in patients with PD receiving optimal dopaminergic therapy. However, these effects have proven difficult to demonstrate on a consistent basis, and further clinical trials are required to establish the clinical utility of this drug class. Based on preclinical studies, A2AAR antagonists may also be neuroprotective and have utility in the treatment of neuropsychiatric disorders. We are only now starting to explore the range of potential uses of A2AAR antagonists in central nervous system disorders, and their full utility is still to be uncovered.