Worldwide, cardiovascular disease (CVD) is the leading cause of death. Most CVD-related deaths are caused by years of preceding atherogenesis and the extensive development of atherosclerotic plaques, some of which may rupture to cause myocardial infarction. Macrophages are known to have a role in almost all stages of atherosclerosis, by both initiating atherosclerotic plaques and degrading them through the secretion of proteolytic enzymes leading to rupture. This review summarizes the literature on the role of macrophages and their proteolytic activity on proteins in the extracellular matrix (ECM) of the atherosclerotic plaque with a view to suggest a novel approach for identification of vulnerable plaques and turnover by the use of a new type of biomarker. The PubMed database was searched using the terms macrophages, foam cells, atherosclerosis, CVD, ECM remodeling, biomarker, neoepitope, matrix metalloproteinase (MMP), and protease. Atherosclerotic plaques are primarily composed of the protein type I and III collagen, and smaller quantities of elastin and proteoglycans. Macrophages secrete an array of proteases, including MMPs, cathepsins, and aggrecanases, with the ability to degrade most of the constituents of the ECM of the atherosclerotic plaque. At present it is not clear which proteases play pivotal roles at distinct stages of pathogenesis, rather that the combined proteolytic potential with some proteases at early stages and other at later stages may result in plaque rupture. This macrophage-mediated proteolysis and remodeling of the ECM play important roles in many stages of atherosclerosis. The degradation fragments of these ECM events are specific neoepitopes, which are released into the circulation. The identification of these pathologically relevant neoepitopes leads to novel biomarkers able to identify the formation and degradation of plaques providing different biological information than traditionally used biomarkers.