Oxygen and nitrogen derived free radicals play a crucial role in both cardiac physiology and pathology. In this review we discuss how these molecules interact in the cardiac cell, some aspects of their physiological importance, and their pathological effects with a special focus on the activation of matrix metalloproteinases (MMPs) as an early event in oxidative stress damage. MMPs are a family of zinc-dependent endopeptidases which play an active role in regulating the extracellular matrix. Recently, however, it has been recognized that MMPs may also rapidly act on intracellular substrates on a minutes timescale. This review will consider some recent developments in the intracellular localization and novel substrates of MMP-2 within the heart. In addition, we will discuss MMP inhibition as a novel therapeutic strategy to prevent oxidative stress damage to the heart.