Many xenobiotics are able to induce liver steatosis, also referred to as fatty liver. This liver lesion is benign, but it can progress in the long term to steatohepatitis characterized by necroinflammation and fibrosis. The occurrence of steatohepatitis is a major issue because it can evolve toward extensive fibrosis, cirrhosis, and even hepatocellular carcinoma. It has been acknowledged that mitochondrial dysfunction is a major mechanism whereby xenobiotics can induce steatosis and steatohepatitis. Inhibition of mitochondrial fatty acid oxidation is responsible for fat accretion, and impairment of the respiratory chain activity can favor the progression of steatosis to steatohepatitis via reduced ATP levels and reactive oxygen species overproduction. There also is increasing evidence that some steatogenic xenobiotics can worsen nonalcoholic fatty liver disease (NAFLD), a large spectrum of liver lesions occurring in the context of obesity and type 2 diabetes. These xenobiotics can either aggravate the intrahepatic accumulation of fat or accelerate the progression of fatty liver to nonalcoholic steatohepatitis. Mitochondrial dysfunction is deemed to be one important mechanism involved in NAFLD worsening. © 2019 Elsevier Inc. All rights reserved.