The fatty acid translocase (FAT)/CD36 belongs to the class B scavenger receptor family. In addition to the known functions of CD36 in the uptake of oxidized low-density lipoprotein by macrophages and uptake of fatty acids by adipose tissues, skeletal muscle and heart, emerging evidence has pointed to an equally important function of CD36 in the uptake of fatty acids in the liver and the pathogenesis of fatty liver disease. Recent reports have also suggested CD36 as a shared transcriptional target of several ligand-sensing and lipogenic transcriptional factors, such as the aryl hydrocarbon receptor, and several nuclear hormone receptors, such as pregnane X receptor, liver X receptor and peroxisome proliferator activated receptor γ. Non-alcoholic fatty liver disease is common and medically significant, because it is closely related to metabolic syndrome and has a potential to progress into the more harmful non-alcoholic steatohepatitis. It is hoped that CD36 and their transcriptional regulators can represent novel therapeutic targets for the prevention and management of fatty liver disease.