This review article discusses the historical origin of cardiac radionuclide-based methods, the physiologic background that justifies their existence, as well as the basic pathophysiologic concepts of coronary artery disease and their connection with the technologic design and application of these methods. Most importantly, this review discusses the important insights that these methods have provided to the understanding of the mechanisms of ischemia, risk stratification, and both treatment choice and treatment efficacy in ischemic heart disease. Nuclear cardiology originated as an attempt to provide complementary physiologic information to the anatomic information provided by coronary angiography. To comprehend the design and applications of nuclear cardiology methods, one must have a basic understanding of coronary artery disease as an inflammatory process that may manifest as acute or chronic states. Basic concepts on myocyte metabolic pathways, coronary blood flow, ischemic cascade, ventricular remodeling, and ejection fraction become critical for this purpose. Insights into risk stratification may permit patient-tailored therapy approaches. Insights into prognosis have made nuclear cardiology a robust tool for outcome predictions, with an exceptionally high negative predictive value. Evaluation of prognosis in special patient populations such as diabetics has originated important pathophysiologic concepts. Most insights into phenomena such as myocardial hibernation, myocardial stunning, and viability have been generated by nuclear cardiology techniques. Finally, new applications of radionuclide-based methods such as molecular identification of "vulnerable" atherosclerotic plaques, "ischemic memory" using fatty acid imaging, and myocardial innervation imaging provide new avenues for insightful research.