A3 Adenosine receptors (ARs) exhibit large species differences. Potent, selective agonists for rat (e.g. Cl-IB-MECA, 5) and human A3 ARs (e.g. PENECA, 17, and analogs) have been developed during the past years. Potent, selective antagonists for human A3 ARs include the imidazopurinones PSB-10 (28) and PSB-11 (29), the pyrazolotriazolopyrimidines MRE-3005F20 (38) and analogs, and the dihydropyridines (e.g. MRS-1334, 50). For rat A3 ARs only moderately potent antagonists have been identified, such as the pyridine derivative MRS-1523 (51) and the flavonoid MRS-1067 (52), both of which exhibit only a low degree of selectivity versus the other AR subtypes. Selective antagonist radioligands for the human A3 receptor, [3H]MRE- 3008F20 and [3H]PSB-11, have been prepared, while A3-selective agonist radioligands are still lacking. Recent developments also include allosteric modulators, irreversibly binding antagonists, fluorescence-labelled agonists, partial agonists and inverse agonists for A3 ARs. Site-directed mutagenesis and molecular modeling studies have been performed in order to obtain information about the ligand binding site and the process of receptor activation. A3 Adenosine receptors have recently attracted considerable interest as novel drug targets. A3 Agonists may have potential as cardioprotective and cerebroprotective agents, for the treatment of asthma, as antiinflammatory and immunosuppressive agents, and in cancer therapy as cytostatics and chemoprotective compounds. A3 AR antagonists might be therapeutically useful for the acute treatment of stroke, for glaucoma, and also as antiasthmatic and antiallergic drugs, since A3 receptors cannot only mediate antiinflammatory, but also proinflammatory responses. The future development of further pharmacological tools, including potent, selective antagonists for rat A3 receptors and selective agonist radioligands for rat and human receptors will facilitate the evaluation of the (patho)physiological roles of A3 receptors and the pharmacological potential of their ligands.