Atherosclerosis underlies most cardiovascular diseases, and is accepted as a primary cause of mortality worldwide. Proteases have been implicated in the development and progression of atherosclerosis, due to their ability to provoke focal destruction of the vascular extracellular matrix. Members of the metalloproteinase family, especially matrix metalloproteinases (MMPs), and their endogenous tissue inhibitors (TIMPs) have been suggested to perform complex dual roles during late-stage progression and rupture of atherosclerotic plaques. Proposed favourable actions of metalloproteinases include the promotion of vascular smooth muscle growth and survival which stabilises plaques, while conversely extracellular matrix destruction alongside interminable monocyte/macrophage accumulation can encourage plaque rupture. This review provides a summary of the cogent evidence connecting the contribution of individual metalloproteinases to atherosclerotic plaque development, progression, and instability. Topics discussed include structural, functional and cell-specific diversity of MMP members; evidence from animal models of atherosclerosis and comparisons with findings in humans; the dual role of MMPs and the requirement to selectively target individual MMPs; and the need for efficient surrogate markers of MMP inhibition. Accordingly, as our knowledge of the complex roles individual MMPs play especially during the progression and rupture of atherosclerotic plaques expands, new impetus is required for clinical trials evaluating the therapeutic potential of selective MMP inhibition, which could limit cardiovascular morbidity and mortality worldwide.