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Matrix metalloproteinases (MMPs) were identified as early as 1962. Since this seminal finding, this family of zinc-dependent endopeptidases has been studied extensively. This collective work has resulted in delineation of MMP gene and protein structures, the mechanisms of control of MMPs, the action of MMPs on their substrates, and of course their role in normal physiology and their crucial roles in pathophysiology. Stemming from the discovery that MMPs contribute to arthritis, heart disease, and cancer, amongst other diseases, attempts to develop treatment strategies incorporating MMP inhibition have been undertaken. The results of these endeavours have been mediocre, resulting in few FDA-approved MMP inhibitors mostly due to the broad-spectrum nature of these early inhibitors and unwanted side effects of MMP inhibition. The future of exploitation of MMPs in disease lies in the design of more targeted inhibitors; in order to accomplish this, we must all understand the subtle differences between each MMP and their contextual roles. In this chapter, we aim to overview major topics regarding MMPs and what direction we may go in the future.