Critical illness and particularly sepsis are associated with a significant redox imbalance resulting from an increased production of oxidant species and a decrease in endogenous antioxidant defences. In critical patients sources of oxidative stress include the mitochondrial respiratory electron transport chain, xanthine oxidase activation, the respiratory burst associated with neutrophil activation, and arachidonic acid metabolism. Several endogenous antioxidants have been identified including enzymes, like superoxide dismutases and glutathione peroxidase, vitamins and other molecules such as uric acid and bilirubin. Recent studies pointed out the correlations between oxidative stress, systemic inflammatory response and apoptosis. Prospective randomized clinical trials regarding antioxidant therapy in critical illness provide increasing evidence in support of selenium, glutamine and omega-3 fatty acids. In particular selenium seems to improve clinical outcome in terms of infections and organ failure, glutamine has been associated with a significant reduction in infectious complications and omega-3 fatty acids could be particularly efficacious in sepsis. Melatonin is a promising molecule that deserves the attention of future research, as well as vitamin C. Further studies should also try to establish the more beneficial combination of antioxidants, as well as the doses, and the timing of administration. When such problems will be resolved hopefully results about antioxidant therapy in critical illness will be more univocal and promising.