In acute myocardial ischemia (AMI) the optimal treatment is rapid revascularization by angioplasty or pharmacological thrombolysis. While this is essential to resuscitate the ischemic myocardium, it results in further reperfusion injury and extension of the infarction. The main hypothesis for the mechanism of reperfusion injury is the generation of reactive oxygen species (ROS) to such a degree that endogenous antioxidant mechanisms are overcome and tissue injury results. There is growing evidence that ROS-induced injury may continue for weeks to months as a result of activation of apoptosis. In the longer term, this may result in ventricular remodeling and cardiac failure. Although a number of antioxidants have produced beneficial effects in animal models of AMI, none have proved efficacious in subsequent clinical trials. Drugs that are more specific for the source of ROS generation and that are better able to target the sources of oxidant stress may have greater potential for the prevention of reperfusion injury.