A key criterion for the most common chronic liver disease-non-alcoholic fatty liver disease (NAFLD)-is an intrahepatic fat content above 5% in individuals who are not using steatogenic agents or having significant alcohol intake. Subjects with NAFLD have increased plasma concentrations of glucagon, and emerging evidence indicates that subjects with NAFLD may show hepatic glucagon resistance. For many years, glucagon has been thought of as the counterregulatory hormone to insulin with a primary function of increasing blood glucose concentrations and protecting against hypoglycemia. However, in recent years, glucagon has re-emerged as an important regulator of other metabolic processes including lipid and amino acid/protein metabolism. This review discusses the evidence that in NAFLD, hepatic glucagon resistance may result in a dysregulated lipid and amino acid/protein metabolism, leading to excess accumulation of fat, hyperglucagonemia, and increased oxidative stress contributing to the worsening/progression of NAFLD.