Fibroblast growth factor 21 (FGF21) is an emerging regulator of energy homeostasis and a novel target for the development of therapies to treat diabetes, cardiovascular disease, and obesity. FGF21 was discovered in an in vitro high throughput screen. It was later shown to have impressive metabolic pharmacology including glucose, lipid, and body weight lowering effects in a variety of animal models, including non-human primates. When tested clinically an FGF21-based analog demonstrated dramatic efficacy in management of circulating lipids but failed to produce a robust glycemic lowering. The basis of this discrepancy in human study relative to pre-clinical investigations remains a conundrum and an area of active investigation. More recently, FGF1 and related structural analogs have emerged as capable of providing impressive metabolic benefits when administered to mice, and as such proposed as an alternative to FGF21-based therapy. Our work is focused on enhancing the inherent properties of FGF21 and further interrogating the mechanism for FGF1 signaling relative to FGF21.