Purpose of Review: Cardiac nuclear imaging is widely used to guide clinical management. While a large body of evidence supports the use of a single set of images, a significant proportion of patients undergo serial studies. The purpose of this review is to highlight recent clinical developments in the serial use of cardiac nuclear imaging and discuss the challenges of interpreting and applying the results. Recent Findings: Serial myocardial perfusion imaging studies have demonstrated the impact of coronary revascularization on myocardial blood flow and established the prognostic value of changes in myocardial perfusion over time. Recent studies have suggested the potential for improved targeting of myocardial revascularization by using positron emission tomography or by focusing on necrosis evaluation instead of traditional viability assessment on imaging. Serial nuclear imaging of cardiac adrenergic function is currently being studied for clinical utility in applications such as detecting early chemotherapy-induced cardiotoxicity or monitoring the effects on the myocardium of mechanical unloading by ventricular assist devices. Although well established for the diagnosis of cardiac transthyretin amyloidosis, technetium pyrophosphate imaging has only recently been evaluated for potential utility of serial evaluations for monitoring the progression of disease. Summary: Over the last few years, we have witnessed increased interest in serial imaging. The use of serial nuclear imaging in the clinical arena will continue to drive research in this field in the foreseeable future to allow us to better understand its implications on clinical care.