Adenosine A2A 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 A2A 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 A2A receptors causes a decrease in D2 receptor-mediated neurotransmission. Thus, drugs that act on A2A 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 A2A receptor antagonists can be used to delineate the physiological and pathological processes regulated by A2A receptors. Results from in vitro and in vivo pharmacology studies strengthen the notion that A2A receptors are an interesting target for drug development.