Reactive oxygen-nitrogen species play important roles in physiological and pathological processes in the heart. This review will focus on the activation of matrix metalloproteinases (MMPs) as a result of oxidative stress, and the consequences of this on heart function. Although the MMPs are considered to be secreted proteases acting on the extracellular matrix to effect tissue remodeling, it is now recognized that MMPs also rapidly act on intracellular protein targets to cause intracellular protein remodeling. Of the 23 known human MMPs, MMP-2 is widely expressed in almost all cell types, is one of the most abundant MMPs in cardiac tissue, and recent evidence has revealed mechanisms by which it is a bona fide intracellular protein. This review will discuss the intracellular localization and novel substrates of MMP-2 within the heart, how intracellular protein proteolysis leads to cardiac dysfunction, as well as the potential of MMPs inhibitors as therapy for cardiovascular diseases caused by enhanced reactive oxygen-nitrogen species.