Atherosclerosis leads to blockage of arteries, culminating in myocardial infarction, and stroke. The involvement of matrix-degrading metalloproteinases (MMPs) in atherosclerosis is established and many studies have highlighted the importance of various MMPs in this process. MMPs were first implicated in atherosclerosis due to their ability to degrade extracellular matrix components, which can lead to increased plaque instability. However, more recent work has highlighted a multitude of roles for MMPs in addition to breakdown of extracellular matrix proteins. MMPs are now known to be involved in various stages of plaque progression: from initial macrophage infiltration to plaque rupture. This chapter summarizes the development and progression of atherosclerotic plaques and the contribution of MMPs. We provide data from human studies showing the effect of MMP polymorphisms and the expression of MMPs in both the atherosclerotic plaque and within plasma. We also discuss work in animal models of atherosclerosis that show the effect of gain or loss of function of MMPs. Together, the data provided from these studies illustrate that MMPs are ideal targets as both biomarkers and potential drug therapies for atherosclerosis.