Excessive production of reactive oxygen species has been implicated to play an important role in a number of cardiovascular pathologies, including hypertension, atherosclerosis, myocardial infarction, ischemia/reperfusion injury, and restenosis after angioplasty or venous bypass grafting. The formation of reactive oxygen species is balanced out by antioxidant defenses, and augmenting this defense by antioxidant therapies could therefore provide a potential means to treat conditions in which the formation of reactive oxygen species exceeds the capability of natural protective mechanisms. In this review, we summarize the studies in which antioxidant gene therapy has been used successfully to treat cardiovascular diseases. We also discuss the current limitations of antioxidant gene therapy and envision future therapeutic targets and methodological approaches for an improved outcome.