Adenosine has often been cited as a universal retaliatory metabolite against the destructive cellular mechanisms that are initiated during metabolic/oxidative stress. Despite this billing, clinical application of adenosine has been limited to rather specific cardiovascular indications (e.g., paroxysmal supraventricular tachycardia). At least four adenosine receptor subtypes mediate the physiologic effects of adenosine, and each receptor subtype has been implicated as a target for development of agonist- and antagonist-based therapies against a wide range of disorders (cardiac arrhythmias, asthma, renal failure, and inflammation). Yet, clinical application of receptor subtype selective ligands has been very limited. The lag in clinical development of subtype selective ligands has largely been due lack of an X-ray resolved receptor structure and concomitant production of very selective agonists and antagonists. Species and tissue differences in ligand selectivity, receptor-effector coupling, and intracellular signaling also frustrate efforts in developing subtype selective therapies despite a great deal of amino acid homology across the receptor subtypes. The adenosine subtype-1 receptor (A1) has been particularly well studied in a variety of cardiovascular pathologies and a number of selective ligands for the receptor have been developed. A1 selective ligands acting as full agonists (CVT-510) or partial agonists (CVT-2759), antagonists (BG9719/CVT-124) and allosteric enhancers (PD81723) are now under preclinical scrutiny or are being developed for the clinical application in a variety of cardiovascular disorders and will be discussed herein.