Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent disease without any approved treatment to-date despite intensive research efforts by researchers and pharmaceutical industry. Fibroblast growth factor (FGF)-21 has been gaining increasing attention as a possible contributing factor and thus therapeutic target for obesity-related metabolic disorders, including NAFLD, mainly due to its effects on lipid and carbohydrate metabolism. Most animal and human observational studies have shown higher FGF-21 concentrations in NAFLD than non-NAFLD, implying that FGF-21 may be increased to counteract hepatic steatosis and inflammation. However, although Mendelian Randomization studies have revealed that variations of FGF-21 levels within the physiological range may have effects in hyperlipidemia and possibly nonalcoholic steatohepatitis, they also indicate that FGF-21, in physiological concentrations, may fail to reverse NAFLD and may not be able to control obesity and other diseases, indicating a state of FGF-21 resistance or insensitivity that could not respond to administration of FGF-21 in supraphysiological concentrations. Interventional studies with FGF-21 analogs (eg, pegbelfermin, efruxifermin, BOS-580) in humans have provided some favorable results in Phase 1 and Phase 2 studies. However, the definite effect of FGF-21 on NAFLD may be clarified after the completion of the ongoing clinical trials with paired liver biopsies and histological endpoints. The aim of this review is to critically summarize experimental and clinical data of FGF-21 in NAFLD, in an attempt to highlight existing knowledge and areas of uncertainty, and subsequently, to focus on the potential therapeutic effects of FGF-21 and its analogs in NAFLD.