Appreciation of the molecular and cellular processes of atherosclerosis, thrombosis, and vascular inflammation has identified new targets for imaging. The common goals of molecular imaging approaches are to accelerate and refine diagnosis, provide insights that reveal disease diversity, guide specific therapies, and monitor the effects of those therapies. Here we undertake a comparative analysis of imaging modalities that have been used in this disease area. We consider the elements of contrast agents, emphasizing how an understanding of the biology of atherosclerosis and its complications can inform optimal design. We address the potential and limitations of current contrast approaches in respect of translation to clinically usable agents and speculate on future applications.