Nonalcoholic fatty liver disease (NAFLD) covers a spectrum of liver damage ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. To date, no pharmacological treatment is approved for NAFLD/NASH. Here, we report on preclinical and clinical data with GFT505, a novel dual peroxisome proliferator‐activated receptor alpha/delta (PPAR‐α/δ) agonist. In the rat, GFT505 concentrated in the liver with limited extrahepatic exposure and underwent extensive enterohepatic cycling. The efficacy of GFT505 was assessed in animal models of NAFLD/NASH and liver fibrosis (Western diet [WD]‐fed human apolipoprotein E2 [hApoE2] transgenic mice, methionine‐ and choline‐deficient diet‐fed db/db mice, and CCl₄‐induced fibrosis in rats). GFT505 demonstrated liver‐protective effects on steatosis, inflammation, and fibrosis. In addition, GFT505 improved liver dysfunction markers, decreased hepatic lipid accumulation, and inhibited proinflammatory (interleukin‐1 beta, tumor necrosis factor alpha, and F4/80) and profibrotic (transforming growth factor beta, tissue inhibitor of metalloproteinase 2, collagen type I, alpha 1, and collagen type I, alpha 2) gene expression. To determine the role of PPAR‐α‐independent mechanisms, the effect of GFT505 was assessed in hApoE2 knock‐in/PPAR‐α knockout mice. In these mice, GFT505 also prevented WD‐induced liver steatosis and inflammation, indicating a contribution of PPAR‐α‐independent mechanisms. Finally, the effect of GFT505 on liver dysfunction markers was assessed in a combined analysis of four phase II clinical studies in metabolic syndrome patients. GFT505 treatment decreased plasma concentrations of alanine aminotransferase, gamma‐glutamyl transpeptidase, and alkaline phosphatase. Conclusion: The dual PPAR‐α/δ agonist, GFT505, is a promising liver‐targeted drug for treatment of NAFLD/NASH. In animals, its protective effects are mediated by both PPAR‐α‐dependent and ‐independent mechanisms. (Hepatology 2013; 58:1941–1952)