Milestones in the progression to heart failure following myocardial infarction (MI) are changes in left ventricular (LV) geometry and function, termed post-MI remodeling. Critical to this adverse remodeling process are changes in the expression, synthesis, and degradation of myocardial extracellular matrix (ECM) proteins. The myocardial ECM is not a passive entity but a complex and dynamic microenvironment that represents an important structural and signaling system within the myocardium. In particular, basic and clinical studies have provided conclusive evidence that abnormal and persistent activation of the ECM degradation pathway, notably through the matrix metalloproteinases (MMPs), contribute to adverse post-MI remodeling. This review examines recent clinical studies that provide further support to the hypothesis that a specific portfolio of MMPs are diagnostic and likely contributory to LV remodeling and the progression to heart failure after MI. Future translational and clinical research focused on the molecular and cellular mechanisms regulating ECM structure and function likely will contribute to an improved understanding of post-MI LV remodeling and yield novel therapeutic targets.