During and after surgical procedures, there is a well defined physiological stress response that involves activation of inflammatory, endocrine, metabolic, and immunological mediators. Oxidative stress, which is defined to be a situation where the production of reactive oxygen/nitrogen species exceeds the mechanisms required to detoxify them, is believed to be an integrated part of the surgical stress response. Oxidative stress per se may be associated with complications such as myocardial injury, sepsis, pulmonary edema, kidney and liver failure, and increased mortality. Melatonin is a potent antioxidant and in many studies melatonin has been shown to be more effective than some "classical" antioxidants (e.g., vitamins E and C) in protecting against oxidative/nitrosative stress. There are numerous experimental studies in which the antioxidant properties of melatonin have been proven. In preliminary studies in newborns with asphyxia, sepsis, or respiratory distress syndrome, melatonin has proven to be a highly potent antioxidant. This review summarizes the results of animal and human studies wherein melatonin was shown to modulate oxidative stress; this discussion emphasizes the stress response related to surgery.