FGF21 is a member of the endocrine FGF family that was identified through genomics and initially lacked a biologic function. Subsequent studies showed that it could increase glucose uptake in adipocytes, and that its expression was increased dramatically in liver of mice eating a ketogenic diet or when fasted. While FGF21 expression was initially thought to be limited to adipose tissue and liver, recent work shows that FGF21 is expressed in multiple tissues, including brown adipose tissue and pancreas, and is capable of regulating multiple metabolic processes. FGF21 plays a key role regulating oxidation of fatty acids in the liver and browning of specific white adipose tissue depots.  Although obesity appears to be a state of FGF21 resistance, when administered systemically, FGF21 increases energy expenditure and is associated with weight loss in models of  both diet induced and genetic obesity. In addition, FGF21 improves glucose control in several diabetic models. Mice lacking FGF21 demonstrate the important role of this molecule in metabolic adaptation. In humans the role of FGF21 is still poorly understood, however circulating levels are increased in a number of clinical situations including obesity and fatty liver. Given the range of metabolic actions and the beneficial effects on weight and glucose we conclude that FGF21 is an “omnikine” with therapeutic potential.