The physiological role of the adenosine A3 receptor is being investigated using newly synthesized, selective ligands. Recently, in addition to agonists, selective antagonists have been developed that belong to three distinct, non-purine chemical classes: flavonoids, 1,4-dihydropyridine derivatives (e.g. MRS1191, which is 1300-fold selective for human adenosine A3 vs A1/A2A receptors, with a Ki value of 31 nM) and the triazoloquinazolines (e.g. MRS1220, which has a Ki value of 0.65 nM). The A3 receptor has proven enigmatic in terms of antagonist ligand specificity, coupling to second messengers, and biological effects in the CNS, inflammatory system and cardiovascular system. A3 receptors are also potentially involved in apoptosis. It appears that intense, acute activation of A3 receptors acts as a lethal input to cells, while low concentrations of A3 receptor agonists protect against apoptosis. Here, Kenneth Jacobson describes how A3 receptor agonists might be useful in treating inflammatory conditions, possibly through their inhibition of tumour necrosis factor alpha (TNF-alpha) release, which has been shown in macrophages. A3 receptor antagonists might be useful in treating asthma or acute brain ischaemia. Recently, the versatility of A3 receptor agonists, administered either before or during ischaemia, in eliciting potent cardioprotection has been shown.