The Gs-coupled A2A adenosine receptor (A2AAR) has been explored extensively as a pharmaceutical target, which has led to numerous clinical trials. However, only one selective A2AAR agonist (regadenoson, Lexiscan) and one selective A2AAR antagonist (istradefylline, Nouriast) have been approved by the FDA, as a pharmacological agent for myocardial perfusion imaging (MPI) and as a cotherapy for Parkinson's disease (PD), respectively. Adenosine is widely used in MPI, as Adenoscan. Despite numerous unsuccessful clinical trials, medicinal chemical activity around A2AAR ligands has accelerated recently, particularly through structure-based drug design. New drug-like A2AAR antagonists for PD and cancer immunotherapy have been identified, and many clinical trials have ensued. For example, imaradenant (AZD4635), a compound that was designed computationally, based on A2AAR X-ray structures and biophysical mapping. Mixed A2AAR/A2BAR antagonists are also hopeful for cancer treatment. A2AAR antagonists may also have potential as neuroprotective agents for treatment of Alzheimer's disease.