State-of-the-art techniques have been used to measure key aspects of cardiovascular pathophysiology from the birth of radionuclide cardiovascular imaging. However, during the last 30 years, there have been few innovative imaging advances to further our understanding of the complex physiologic processes. Molecular imaging now offers an array of tools to develop advanced diagnostic approaches and therapies for patients with coronary artery disease and heart failure. For example, the enhanced understanding of the pathophysiology of atheroma makes it possible to identify vulnerable plaque based on its metabolic signature or the presence of excessive apoptosis. Because the metabolic and apoptotic signals are large, it is likely that even small lesions will be visible. Of the many approaches that are being developed, 2 tracers appear most likely to be tested in the near future: (1) [18F]-fluorodeoxyglucose, to determine macrophage metabolism; and (2) radiolabeled annexin, to measure apoptosis of the inflammatory cells. Using existing techniques such as perfusion imaging, appropriate patients can be selected for treatment with novel therapies, such as stem cell transplantation or vascular gene therapy. Using positron tomography in place of single photon imaging adds the capability for the measurement of absolute perfusion and perfusion reserve to the information on regional perfusion. Flow reserve detects global decreases in perfusion and refines the determination of lesion severity available from perfusion imaging.