Given the worldwide increase in obesity and diabetes, non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease. NAFLD is associated with increased hepatic and extrahepatic morbidity and mortality, mainly related to non-alcoholic steatohepatitis with fibrosis. An early diagnosis in the high-risk population with features of insulin resistance and a proper identification of those patients with progressive liver disease are needed. Practicing physicians dealing with NAFLD should be aware of and should carefully evaluate the extended spectrum of NAFLD-related extrahepatic diseases, which significantly affects liver- and non-liver-related prognosis. This clinical practice-oriented article reviews the diagnostic methods and staging strategies for NAFLD and proposes an investigational algorithm for a global evaluation of NAFLD patients.