The utility of stress myocardial perfusion imaging (MPI) for the diagnosis and prognosis of coronary artery disease (CAD) has been firmly established in numerous clinical studies and has become an essential component of clinical practice. Stress MPI is now used regularly to guide initial risk stratification and management of patients with CAD. Because stress MPI provides an assessment of the physiologic significance of CAD, it is a particularly attractive procedure for assessing follow-up risk. Today, sequential stress MPI is being used increasingly to track disease progression, assess follow-up risk, detect restenosis following revascularization, and evaluate the efficacy of aggressive medical therapy and risk-factor modification. By providing serial snapshots of the disease and its impact on perfusion, sequential stress MPI may alter treatment decisions and ultimately improve long-term patient management and outcomes. Use of sequential stress MPI to detect changes in perfusion following surgical or medical therapies is being tested currently in the Clinical Outcomes Using Revascularization and Aggressive Drug Evaluation (COURAGE) and Adenosine Sestamibi Single-Photon Emission Computed Tomography Postinfarction Evaluation (INSPIRE) trials.