Adenosine A_2A receptors, which have been cloned from several mammalian species, are activated by physiological concentrations of adenosine to stimulate the formation of cAMP and other mediators. The A_2A receptors are found on neutrophil leukocytes, platelets, blood vessels and, very abundantly, on some cells in the CNS. In the caudate nucleus they coexist with dopamine D₂ receptors, and stimulation of A_2A receptors causes a decrease in D₂ receptor-mediated neurotransmission Thus, drugs that act on A_2A receptors can be used to modify dopaminergic neurotransmission known to be important in neurological and psychiatric disorders. In this review, Ennio Ongini and Bertil Fredholm describe how recently developed potent and selective A_2A receptor antagonists can be used to delineate the physiological and pathological processes regulated by A_2A receptors. Results from in vitro and in vivo pharmacology studies strengthen the notion that A_2A receptors are an interesting target for drug development.