Fatty liver disease (FLD) ranges from simple liver fat accumulation to more severe conditions like inflammation, fibrosis and ultimately cirrhosis and cancer. Despite all the efforts, to date there is no approved drug treatment against this disease. Obesity is the strongest environmental risk factor for FLD. However, some individuals, despite being obese, do not have hepatic fat accumulation or, even more surprisingly, although with liver fat, do not progress towards the more severe stages of FLD. Our aim is to understand the protection against FLD and its progression in obese individuals by: A) unravelling the mechanisms behind the beneficial effect of genetic variants protecting against FLD; B) identifying novel protective genetic variants; and C) identifying specific lipid species and metabolic pathways protecting against disease progression. This will finally allow us to identify novel targets and compounds to effectively treat FLD in a framework of precision medicine.