Accumulating evidence links catastrophic cardiovascular events to the inflammatory, angiogenic, and apoptotic biological profiles underlying high-risk atherosclerotic plaques. While biological detail is opaque to traditional anatomical imaging readouts, emerging molecular imaging approaches are now yielding significant clinical insights into the biological diagnosis, characterization, and treatment of atherosclerotic vascular disease. Yet, while clinical molecular imaging approaches are available for larger arterial beds such as the carotid arteries or aorta, molecular imaging pathways for human coronary arterial plaques are lacking. Excitingly, the recent advent of intravascular near-infrared fluorescence technology now offers new potential for in vivo molecular imaging of key molecular and cellular targets in coronary-sized vasculature. Here we provide a framework for coronary artery–targeted molecular imaging using intravascular imaging technology, and present key molecular imaging targets relevant to the detection of high-risk, vulnerable coronary plaques.