Adenosine is a ubiquitous extracellular signaling molecule with essential functions in human physiology. Due to the widespread expression of adenosine receptors, it has far-reaching effects across many different organ systems. With a prominent role in the cardiovascular system, it has been extensively studied for both its therapeutic and diagnostic abilities. One of the key areas of use is in the coronary circulation whereby adenosine produces a hyperemic response. An important target of adenosine is the coronary microcirculation whereby adenosine acts as a prominent vasodilator with many of the beneficial effects of adenosine reflected in its capacity to affect the microvessels. Adenosine also has an important role in the pre-conditioned state and also in the attenuation of ischemia-reperfusion injury. This review examines the physiology, pharmacology, and therapeutic applications of adenosine in the human cardiovascular system and provides a brief overview of important aspects of the adenosine-cardiac interaction. It also examines the role of adenosine in the coronary hyperemic response and discusses the use of adenosine for this purpose. After recent concerns about the use of adenosine, a discussion regarding safety of this drug is provided. A brief review of novel agents used to initiate coronary hyperemia is also provided.