With nonalcoholic steatohepatitis (NASH), NASH cirrhosis, and NASH-related hepatocellular carcinoma becoming increasingly prevalent, the need for effective therapies has never been greater. Unfortunately, our understanding of what causes NASH at the molecular level remains mostly speculative, and thus our ability to design clinical trials that test rationally designed therapies is limited. More than a decade has passed since Christopher Day and Oliver James first proposed the oft-cited twohit hypothesis of nonalcoholic fatty liver disease (NAFLD) to explain the pathogenesis of NASH. 2, 3 According to this appealing hypothesis, the accumulation of lipid in the form of triglyceride is needed for the development of NASH and thus constitutes the first ‘‘hit’’in this disease. The cause of injury in the setting of lipid-loaded hepatocytes was proposed to be oxidant stress leading to lipid peroxidation in the milieu of ample substrate. This second ‘‘hit’’then triggers the necroinflammatory changes that we recognize histopathologically as NASH.