This review is part of a special issue dealing with various aspects of non-alcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). We will focus on promising treatments of NASH with antioxidants and drugs that interfere with lipid metabolism.The other therapies of interest, such as diet, behavioral changes, and insulin sensitizers are presented elsewhere. Oxidative stress is believed to play a key role in the pathogenesis of NASH and other liver diseases. Antioxidants aimed at improving chronic alcoholic or viral liver diseases have been an object of study for some time. However, only a few high quality, randomized, versus placebo-controlled, double-blinded trials have been carried out to assess these drugs. Vitamin E is currently the most widely assessed antioxidant. Several questions need to be answered, including long-term tolerance and efficacy of vitamin E in particular subsets, such as diabetes and NASH-related cirrhosis. Other antioxidants are promising, and should be assessed using the standards of evidence-based medicine. NAFLD frequently coexists with hyperlipidemia and carries an increased risk of cardiovascular disease (CVD). Furthermore, altered lipid metabolism is thought to be central to the pathogenesis of liver injury in NASH. Therefore, lipid-lowering drugs are attractive therapeutic tools in the treatment of NAFLD. Statins have ameliorated surrogate markers of steatosis in several randomized controlled trials, but their impact on liver histology is unknown. They have, however, been found to be the only class of lipid-lowering drugs that reduces cardiovascular risk in NAFLD. Preliminary evidence suggests that ezetimibe, an inhibitor of intestinal and hepatic cholesterol absorption, may improve liver histology, but its impact on the risk of CVD and on clinical outcome remains to be determined. Despite strong experimental evidence supporting the use of omega-3 polyunsaturated fatty acids in NAFLD, the studies published on humans have consisted of small sample sizes and had a number of methodological flaws, including the absence of post-treatment histology. Association of antioxidants and/or lipid-lowering drugs plus other drugs of interest in NASH, such as insulin sensitizers, warrant investigation. However, as promising as these drug treatments may continue to be, they should be associated with diet and modifications in lifestyle.