Major depressive disorder is a common mental disorder. Increasing evidences suggests that major depression is associated with increased oxidative stress and lipid peroxidation. Many studies indicate that, reactive oxygen species induce neuronal damage and they have an important role in the pathophysiology of depression. Oxidative stress is defined as the imbalance between production of reactive oxygen species (superoxide radical, hydrogen peroxide and hydroxyl radical) and reactive nitrogen species (peroxynitrite, ONOO-) and their insufficient decomposition by the antioxidative defense system. In normal physiological conditions, reactive oxygen species and reactive nitrogen species are produced continuously and they are effectively controlled or eliminated by intracellular and extracellular antioxidant defense systems. This antioxidative defense systems involves enzymatic antioxidants; superoxide dismutase, glutathione peroxidase, glutathione reductase, catalase, and paraoxonase and nonenzymatic antioxidants; reduced glutathione, provitamin A, vitamin C and E, coenzyme Q10, carotenoids and trace elements like copper, zinc or selenium. High oxygen consumption, high amount of polyunsaturated fatty acids and iron and low activities of antioxidant enzymes makes sensitive brain to oxidative damage. In high concentrations, reactive oxygen species lead to damage of components of the cell, including proteins, lipids and DNA. Antidepressants are widely used in the treatment of major depression and other psychiatric disorders and their use are increasing with each passing day. The exact mechanisms of action of antidepressants are unknown but they may act by suppressing production of several proinşammatory cytokines and reactive oxygen species, reactive nitrogen species or enhancing antioxidant defense systems such as antioxidant enzymes. In vitro studies were conducted to investigate the antidepressants effects on antioxidant and oxidant system. These studies revealed antioxidant related effects and their protective effects against oxidative stress for antidepressant drugs. Moreover, it has been suggested that, some antidepressants may be pro-oxidant at high doses in in vitro studies. In animal studies, different animal models were used to investigate the oxidant and antioxidant effects of antidepressant drugs. Most of animal studies suggested that antidepressant drugs decrease oxidative stress and modulate the antioxidant enzyme activities. In recent years, an increasing number of studies have focused on the potential effects of antidepressant treatments on oxidative stress and antioxidant status in humans. Most of human studies have shown that, antidepressant drugs have antioxidant properties and they reduce increased oxidative stress, when they are used to treat the patients, in consistency with the findings of in vitro and animal studies. Also in some studies, antidepressants did not modify any oxidative and antioxidative parameters or induced oxidative stress in patients. Therefore, to elucidate the effects of antidepressants on oxidative and nitrosative stress we need the well-designed studies. In addition, it has been shown that some of the classic antioxidants causes antidepressant like effects and these are indicates us new targets for antidepressant treatment.