Heart failure (HF) is a major health problem, causing significant morbidity and mortality. Its complex pathophysiology has not yet been fully elucidated. There is growing evidence that oxidative stress is implicated in the cardiac dysfunction leading to HF. In addition, several components of neurohormonal activation, such as catecholamines, angiotensin, aldosterone, tumor necrosis factor-a, endothelin, and cytokines, have been demonstrated to enhance oxidative stress. On the other hand, various pathophysiological parameters of HF, such as cardiomyocyte apoptosis, ventricular remodeling, mechanoelectric uncoupling, and endothelial dysfunction have been shown to be induced by oxidative stress. Despite substantial experimental evidence, the correlation of oxidative stress with the clinical parameters of HF is unclear. The potential association between oxidative stress and HF has led to the study of antioxidant interventions that may attenuate the oxidative damage. Promising results have been obtained mainly from studies using water-soluble antioxidants (such as vitamin C) and factors that inhibit free radical formation (such as allopurinol). The amelioration of oxidative stress in conjunction with pathophysiological abnormalities has been clearly shown in humans, but studies with clinical end-points are scarce. Furthermore, carvedilol and several other cardiovascular drugs, besides their favorable effects on neurohormonal activation in HF, may have additional intrinsic antioxidant properties. Even though the experimental evidence is promising, many more human clinical trials are needed in order to clarify the exact role of oxidative stress in HF and the potential benefits of antioxidant intervention.