The rupture of an atherosclerotic plaque with subsequent thrombotic lumenal occlusion is a primary cause of acute coronary events, accounting for 60% of sudden deaths. The present dogma proposes that inflammatory cells play a major role in the pathophysiology of both atherosclerotic plaque development and rupture. Entrapment of low-density lipoprotein (LDL) within the extracellular matrix (ECM) of the vessel wall results in its modification and oxidation, which instigates an inflammatory response. Leukocytes interact with numerous adhesion molecules, and various cytokines and growth factors secreted from endothelial cells and underlying vascular smooth muscle cells (VSMC), prompting their adhesion, transmigration and maturation. This inflammatory infiltrate triggers a series of events resulting in the formation of a complex atherosclerotic plaque. Such lesions contain a lipid/necrotic core that is highly thrombogenic but is protected from the circulating blood by the VSMC-rich, fibrillar collagen-rich fibrous cap which confers mechanical strength. Thus rupture of an atherosclerotic plaque exposes the thrombogenic lipid core to the circulating blood, initiating thrombus formation that can rapidly occlude the artery, leading to clinical symptoms such as unstable angina, myocardial infarction and stroke. Many of the multifactorial processes that participate to plaque development and destabilisation involve extracellular matrix turnover. Within the normal vessel wall extracellular matrix degradation is tightly regulated through a balance of proteinases and their endogenous inhibitors. However, within the atherosclerotic plaque the balance may become shifted towards matrix degradation, particularly at the rupture-prone shoulder region of the fibrous cap where accumulating inflammatory cells and phenotypically altered smooth muscle cells secrete a plethora of proteinases including matrix metalloproteinases (MMPs). Indeed, studies in human atherosclerotic plaques have suggested a decisive role for MMPs in plaque destabilisation. Similarly, in the atherosclerotic lesions that form in cholesterol-fed rabbits and mice, an increase in MMP secretion and activity paralleled the severity of atheroma formation observed in these models. Subsequently, numerous studies have used genetic manipulation, gene therapy and synthetic MMP inhibitors to dissect the roles MMPs may play during atherosclerotic plaque development and stability in hypercholesteroleamic animals. These studies have demonstrated that MMPs play both beneficial and detrimental roles during atherosclerosis, not just through there capacity to degrade extracellular proteins, but also non-matrix proteins that influence the behaviour of plaque cells such as smooth muscle cells and macrophages. For instance some MMPs can facilitate VSMC migration and subsequent fibrous cap formation whilst others MMPs aid macrophage plaque-infiltration and lipid-core formation, factors known to trigger plaque rupture. The more we learn about the multifactorial events that underlie plaque instability, particularly with regards to the interactions MMPs have with surrounding cellular and extracellular components, the more complicated the whole process appears. For example, smooth muscle cell growth may be beneficial in unstable atherosclerotic plaques, promoting fibrous cap formation, but detrimental in stable lesions by increasing lesion size and stenosis. With this in mind, and considering that utilisation of broad-spectrum MMP inhibitors has additionally highlighted the dual role MMPs play, the generation of more selective MMP inhibitors is warranted, particularly if MMP inhibition is to be considered as a therapeutic target for atherosclerotic plaque stabilisation.