Fibroblast growth factor 21 (FGF21) is an atypical member of the FGF family that functions as an endocrine hormone. Pharmacologic studies show that FGF21 has broad metabolic actions in obese rodents and primates that include enhancing insulin sensitivity, decreasing triglyceride concentrations, and causing weight loss. In lean rodents, FGF21 expression is strongly induced in liver by prolonged fasting through a mechanism that involves the nuclear receptor peroxisome proliferator-activated receptor alpha. FGF21, in turn, induces the transcriptional coactivator protein peroxisome proliferator-activated receptor gamma coactivator protein 1alpha and stimulates hepatic gluconeogenesis, fatty acid oxidation, and ketogenesis. FGF21 also blocks somatic growth and sensitizes mice to a hibernation-like state of torpor. Thus, FGF21 plays a key role in eliciting and coordinating the adaptive starvation response. Interestingly, FGF21 expression is induced in white adipose tissue by peroxisome proliferator-activated receptor gamma, which suggests that it also regulates metabolism in the fed state. This article highlights recent advances in our understanding of FGF21's pharmacologic and physiologic actions.