Oxidant byproducts, such as superoxide anion (O2-) and hydrogen peroxide are produced as a consequence of normal aerobic metabolism. Because they are highly reactive with other biologic molecules, such as protein, DNA, and lipids, they are called as reactive oxygen species (ROS). Fortunately, our body is equipped with numerous potent endogenous antioxidants. Oxidative stress is caused by an imbalance between the production of ROS and the biologic scavenger system, antioxidants. Oxidative-induced damage has been considered to be one of the underlying mechanisms that contribute to multiple organ failure in sepsis. Both enzymatic and nonenzymatic antioxidants have been widely tested in human and animals with sepsis. However, the disappointing results of N-acetylcysteine (NAC), which is the most extensively tested antioxidant may reflect the inability to reestablish a redox balance in the setting of sepsis in patients. Still, three antioxidants demonstrated clinical benefits and reached level A evidence; selenium improves clinical outcome (infections, organ failure); glutamine reduces infectious complication in large-sized trials; and omega-3-fatty acids have significant anti-inflammatory effects. Other antioxidants are still on the clinical benchmark level, awaiting well-designed clinical trial.