In cardiovascular disease rupture of a vulnerable atherosclerotic plaque is the major causative factor of acute coronary syndromes, myocardial infarction and stroke, and can ultimately lead to death. Identification of biomarkers that could accurately predict the risk of plaque rupture would be a significant advance in guiding treatment of patients with this disease, The use of these biomarkers would also facilitate the development of new drugs to treat cardiovascular disease, particularly those that act through novel mechanisms. There is currently a lack of specific biomarkers for vulnerable plaque, and thus, it is an area of intense research including the concepts of live detection versus retrospective characterization, molecular imaging, and biochemical biomarker discovery. This review will focus on recent advances on both imaging and circulating molecular biomarkers in atherosclerosis. The use of combinations of different imaging modalities (such as molecular, functional, and anatomical) and modalities with circulating/biochemical markers is the current trend and will likely provide the most useful information for the assessment of the vulnerability of atherosclerotic plaques.