Non-alcoholic fatty liver disease (NAFLD), the most common liver disorder in the Western world, is a clinico-histopathological entity in which excessive triglyceride accumulation in the liver occurs. Non-alcoholic steatohepatitis (NASH) represents the necroinflammatory form, which can lead to advanced liver fibrosis, cirrhosis, and hepatocellular carcinoma. The pathogenesis of NAFLD/NASH is complex but increased visceral adiposity plus insulin resistance with increased free fatty acids release play an initial key role for the onset and perpetuation of liver steatosis. Further events in the liver include oxidative stress and lipid peroxidation, decreased antioxidant defences, early mitochondrial dysfunction, iron accumulation, unbalance of adipose-derived adipokines with a chronic proinflammatory status, and gut-derived microbial adducts. New gene polymorphisms increasing the risk of fatty liver, namely APOC3 and PNPLA3, have been lately identified allowing further insights into the pathogenesis of this condition. In our review pathophysiological, genetic, and essential diagnostic and therapeutic aspects of NAFLD are examined with future trends in this field highlighted.