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Introduction: Fibroblast growth factor (FGF) 21 is a member of the FGF19 sub-family of signaling molecules. They have been found to act at the localized paracrine/autocrine and systemic endocrine levels because of their extracellular matrix and co-receptor protein binding characteristics. While the molecule circulates systemically, it has specificity conferred by a co-factor binding protein β-Klotho which is preferentially expressed in hepatic and adipose tissues. This protein, in conjunction with the FGF receptor (FGFR), propagates the downstream effects of the growth factor signaling cascade, which has been linked to fat and glucose metabolism. FGF21 has been recognized as a possible pathway for the treatment of nonalcoholic fatty liver disease (NAFLD). Targeting of the FGF21/FGFR/β-Klotho pathway may halt or reverse hepatic fat infiltration, inflammation, and fibrosis.Areas covered: This article summarizes preclinical and clinical data on the efficacy and safety of two FGF21 agonist therapies in development.Expert opinion: Preclinical and clinical data justify further investigation of FGF21 agonist therapies for the treatment of NAFLD. However, issues including injection site reactions and possible effects on bone homeostasis mean that safety must be evaluated carefully.