This article presents the exciting advances made and ongoing in the area of pharmacologic cardiac stress testing. In particular, new A(2A)-specific receptor agonists work like adenosine but promise the delivery of uncomplicated vasodilator stress testing or the diagnosis and prognosis of coronary disease. These agents, although not perfect, do likely present a level of protection against the complications of bronchospasm and heart block. Phase III studies have shown that these agents promise a reduced symptom intensity and greater patient tolerance. One of these agents, regadenoson, is now Food and Drug Administration approved and will be delivered as the same single-dose bolus in all patients, regardless of weight, greatly simplifying the method and increasing its acceptability. Most widely applied with myocardial perfusion SPECT, these agents will find application with PET myocardial perfusion studies and likely MRI studies. Because of their effect on coronary supply rather than demand, they will not be applied with stress echocardiography. Before considering these agents, we will consider the principles and methods of stress testing, and particularly pharmacologic stress testing. The learning objectives of this article are to familiarize the reader with the methods and choices in stress testing for coronary disease diagnosis and prognosis, to present the advantages and disadvantages of pharmacologic stress testing, to review current pharmacologic stress-testing methods and their specific combination with imaging methods, to present the chemistry and effects of the new A(2a)-specific receptor agonists and their advantages compared with existing nonspecific agents, and to help the reader better understand the clinical role of the A(2a)-specific receptor agonists and their application.