Medicinal chemical approaches have been applied to all four of the adenosine receptor (AR) subtypes (A₁, A_2A, A_2B, and A₃) to create selective agonists and antagonists for each. The most recent class of selective AR ligands to be reported is the class of A_2BAR agonists. The availability of these selective ligands has facilitated research on therapeutic applications of modulating the ARs and in some cases has provided clinical candidates. Prodrug approaches have been developed which improve the bioavailability of the drugs, reduce side-effects, and/or may lead to site-selective effects. The A_2A agonist regadenoson (Lexiscan®), a diagnostic drug for myocardial perfusion imaging, is the first selective AR agonist to be approved. Other selective agonists and antagonists are or were undergoing clinical trials for a broad range of indications, including capadenoson and tecadenoson (A₁ agonists) for atrial fibrillation, or paroxysmal supraventricular tachycardia, respectively, apadenoson and binodenoson (A_2A agonists) for myocardial perfusion imaging, preladenant (A_2A antagonist) for the treatment of Parkinson's disease, and CF101 and CF102 (A₃ agonists) for inflammatory diseases and cancer, respectively. This article is part of a Special Issue entitled: Adenosine Receptors.