Cardiovascular diseases are a major burden to society and a leading cause of morbidity and mortality in the developed world. Despite clinical and scientific advances in understanding the molecular mechanisms and treatment of heart injury, novel therapeutic strategies are needed to prevent morbidity and mortality due to cardiac events. Growing evidence reported over the last decade has focused on the intracellular targets for proteolytic degradation by MMP-2. Of particular interest is the establishment of MMP-2-dependent degradation of cardiac contractile proteins in response to increased oxidative stress conditions, such as ischemia/reperfusion. The authors' laboratory has identified a promising preventive therapeutic target using the classical pharmacological concept of synergy to target MMP-2 activity and its proteolytic action on a cardiac contractile protein. This manuscript provides an overview of the body of evidence that supports the importance of cardiac contractile protein degradation in ischemia/reperfusion injury and the use of synergy to protect against it.