Nonalcoholic fatty liver disease (NAFLD) is a metabolic disorder including simple steatosis and nonalcoholic steatohepatitis (NASH). Advanced stages of NASH result ultimately in fibrosis, cirrhosis, and hepatocarcinoma. A diagnosis of NASH entails an increased risk of both liver-related and cardiovascular mortality as worsening of the metabolic syndrome. Because of its escalation, many investigations have been performed to elucidate the pathophysiologic origins of the disease progression. Human epidemiologic studies describing polymorphisms in a number of genes involved in metabolic dysfunctions have contributed to clarify the causes leading to the disease evolution. In this review, we attempt to outline critically the most recently identified genetic variants in NAFLD patients to identify possible risk factors promoting the progression of the disease. The evaluation of altered genotypes together with other clinical variables may facilitate the clinical management of these patients.