Lipid peroxidation and secondary cellular injury are the dominant mechanism in the transition from relatively stable hepatic steatosis to potentially progressive steatohepatitis in nonalcoholic fatty liver disease (NAFLD). Oxidation of excessive fatty acids generates free radicals (reactive oxygen species) that damage organelles and stimulate signaling pathways leading to fibrosis and cellular injury. Both antioxidant agents (by breaking the chain reaction of lipid peroxidation) and cytoprotective agents (by stabilizing cellular and organelle phospholipid membranes) may be effective agents in treating an active steatohepatitis through amelioration of the driving force and attenuation of the secondary effects. Here we have reviewed the existing studies on such therapies, including vitamin E, S-adenosylmethionine (SAMe), betaine, and ursodeoxycholic acid. Small trials suggest possible improvement in liver enzymes with the use of these agents in NAFLD. However, controlled studies have not uniformly demonstrated benefit from these agents when compared with control groups treated with diet and weight loss alone, and measurement of reliable histologic endpoints is limited. These agents may show benefit in NAFLD through future larger controlled studies. Particular promise may exist in the use of these agents in combination therapy with ones that target other aspects in the pathogenesis of NAFLD, such as insulin-sensitizing agents.