The search for potent and selective A2A adenosine receptor agonists has been particularly fruitful in the early nineties. A series of 2-amino, 2-alkoxy, 2-alkythio-, 2-alkynyl-, and 2-alkenyl-derivatives of adenosine (Ado, 1) and N-ethylcarboxamidoadenosine (NECA, 30) have been synthesized and tested mainly on different model of rat A1 and A2A receptor subtypes. From these studies some ligands, such as CGS 21680 (33), HENECA (42), and (S)-PHPNECA (46b), showed to possess high A2A affinity combined with good A2A vs A1 selectivity. More detailed characterization of these ligands at the four cloned human adenosine receptor subtypes revealed that none of the prototypical adenosine receptor agonists exhibits at the same time high affinity and selectivity for the human A2AAR subtype. Both NECA and CGS 21680, which are avalaible as radioligands for this subtype, have lower affinity at human than at rat receptor. The 2-alkynylNECA derivatives HENECA an PHPNECA showed high affinity also at human A3 receptors. In particular, (S)-PHPNECA displayed Kis in the low nanomolar range at A1, A2A, and A3 subtypes and an EC50 of 220 nM at human A2B receptor. On the other hand, it is now well known that the coronary vasodilation induced by Ado in different species is mediated by activation of A2AAR and a compound capable of producing coronary vasodilation through activation of A2AAR, but that is devoid of A1- and A3-agonist activity would have advantage over Ado for use in myocardial perfusion imaging studies. Other potential therapeutic applications of selective A2AAR agonists are as anti-aggregatory, anti-inflammatory, anti-psychotic, and anti-Huntingtons disease agents. This review is aimed at presenting a complete overview of the medicinal chemistry development of A2A adenosine receptor agonists and at stressing the strong need for more selective ligands at A2A human subtype.