Non-alcoholic fatty liver disease (NAFLD) is an emerging metabolic-related disorder characterized by fatty infiltration of the liver in the absence of alcohol consumption. NAFLD ranges from simple steatosis to non-alcoholic steatohepatitis (NASH), which might progress to end-stage liver disease. This progression is related to the insulin resistance, which is strongly linked to the metabolic syndrome consisting of central obesity, diabetes mellitus, and hypertension. Earlier, the increased concentration of intracellular fatty acids within hepatocytes leads to steatosis. Subsequently, multifactorial complex interactions between nutritional factors, lifestyle, and genetic determinants promote necrosis, inflammation, fibrosis, and hepatocellular damage. Up to now, many studies have revealed the mechanism associated with insulin resistance, whereas the mechanisms related to the molecular components have been incompletely characterized. This review aims to assess the potential molecular mediators initiating and supporting the progression of NASH to establish precocious diagnosis and to plan more specific treatment for this disease.