Atherosclerosis and its thrombotic complications represent the major cause of morbidity and mortality in the industrialized countries. Despite recent advances in the diagnosis and management of cardiovascular disease, a substantial number of patients still die from acute coronary syndromes. Recently, atherosclerotic plaque composition rather than the degree of arterial stenosis has been shown to reflect the plaque vulnerability, thus contributing to the pathogenesis of cardiovascular disease. Vulnerable plaques have a large lipidrich necrotic core, a thin-fibrous cap and numerous inflammatory cells. Among them, macrophage activation plays a central role in vascular inflammation and plaque instability within the atherosclerosis, being strongly involved in acute coronary syndromes. Various morphologic features of plaque vulnerability have been described by computed tomography angiography, magnetic resonance imaging, intravascular ultrasound, and optical coherence tomography. Molecular imaging is the tool best suited for identifying metabolically active macrophages. Indeed, positron emission tomography (PET) imaging with 18F-fluorodeoxyglucose (FDG) is capable of identifying and quantifying vascular inflammation characterized by macrophage activation within the atherosclerotic plaques. So, FDG-PET might be a feasible clinical tool for detecting vulnerable plaques and evaluating the efficacy of drugs in plaque instability. In this paper, we review the clinical utility of FDG-PET imaging in identifying patients at risk of plaque rupture and resultantly prone to cardiovascular disease.