Atherosclerotic plaque rupture is the leading cause of acute coronary syndrome. Molecular calcification represent as one of the early stages of plaque evolution has been hypothesized to play a potential role in atherosclerotic plaque instability and subsequent rupture. Several invasive and non-invasive structural imaging techniques have been utilized to diagnose atherosclerosis, but none of these methods are capable of detecting and quantifying molecular calcification. Fluorine-18-Sodium Fluoride (18F-NaF) positron emission tomography/computed tomography (PET/CT) imaging allows detection and quantification of arterial molecular calcification in heart and across multiple vessels. In this review the authors discuss the feasibility, application and potential future of 18F-NaF-PET/CT in detecting molecular calcification and in defining the future risk of atherosclerotic plaque rupture in the affected vessels.