Myocardial perfusion imaging using radionuclides is a well-established protocol for determining the diagnosis, prognosis, and management of coronary artery disease. Pharmacologic stress agents are used to induce cardiac hyperemia in patients unable to achieve the target workload by physical exercise alone. The vasodilators adenosine and dipyridamole are most commonly used, with dobutamine used only when these agents are contraindicated. However, because of frequent and intense side effects, as well as complex procedures both for patients and the nuclear medicine staff, there is room for improvement in these traditional stress agents. An ideal stress agent would be effective, safe, and well tolerated; have a simple protocol; be suitable for use in patients with reactive airway disease; and have few restrictions for the patient to adhere to before the procedure. Neither adenosine nor dipyridamole are receptor-specific, and act on A(1), A(2A), A(2B), and A(3) adenosine receptors. As it is the A(2A) receptor that mediates the desired coronary vasodilation, the A(1), A(2B), and A(3) adenosine receptors are deemed responsible for most side effects associated with adenosine and dipyridamole. A(2A)-selective pharmacologic stress agents should mediate the required hyperemic response while reducing the frequency of adverse events. The only selective A(2A) adenosine receptor agonist currently approved for clinical use as a pharmacologic stress agent for myocardial perfusion imaging is regadenoson. Regadenoson has demonstrated non-inferiority to adenosine for detecting reversible myocardial perfusion defects in phase 3 trials, and patients were more comfortable during the regadenoson stress procedure than during an adenosine infusion. As regadenoson dosing is not dependent on patient weight or renal impairment and can be administered by rapid injection, it has the potential to simplify the stress procedure, reduce costs, and streamline the working day for the staff of the nuclear medicine department. In this review, the need to improve on older pharmacologic stress agents will be considered, along with an assessment of how A(2A) receptor agonists fulfill that potential. Practical aspects of regadenoson are reviewed, and the impact that A(2A) receptor agonist use may have on the nuclear medicine department is evaluated.