The matrix metalloproteinase (MMP) family of enzymes is involved in arterial wall extracellular matrix degradation and remodeling. The latter activities have been implicated in a number of normal and pathologic processes, such as atherosclerotic lesion formation and progression, plaque destabilization and rupture, but also in plaque stabilization and healing. As a result, the MMPs have been explored as both therapeutic targets and diagnostic tools for the treatment and diagnosis of atherosclerotic cardiovascular diseases. In this review, we summarize experimental findings, genetic associations, and the biomarker potential of MMPs in atherothrombosis. In addition, the regulation and expression of MMPs in atherosclerotic plaques is discussed, with an emphasis on the role of lipid-derived inflammatory mediators as modulators of MMP activity.