Previous basic, clinical, and population sciences have advanced the modern treatment of heart failure. An approach to solve this crucial issue is the further development of novel therapeutic strategies based on a novel insight into the pathophysiology of myocardial remodeling and failure. Recent experimental and clinical studies have suggested that oxidative stress is enhanced in heart failure. The production of oxygen radicals is increased in the failing heart whereas antioxidant enzyme activities are preserved in the normal heart. Mitochondrial electron transport is an enzymatic source of oxygen radical generation and also a target against oxidant-induced damage. Chronic increases in oxygen radical production in the mitochondria can lead to a catastrophic cycle of mitochondrial DNA damage as well as functional decline, further oxygen radical generation, and cellular injury. These cellular events might play an important role in the development and progression of myocardial remodeling and failure. Therefore, mitochondrial oxidative stress and DNA damage are good therapeutic targets. This approach may lead to establish the novel and most effective treatment strategies for patients with heart failure.