Growth differentiation factor-15 (GDF15) is a circulating protein that has been implicated in multiple biological processes, including energy homeostasis, body weight regulation, and cachexia driven by cancer and chronic disease. The potential to target GDF15 in the treatment of energy-intake disorders, including obesity and anorexia, is an area of intense investigation, but has been limited by the lack of an identified receptor, signaling mechanism, and target tissue. GDNF family receptor α-like (GFRAL) was recently identified as the neuronal brainstem receptor responsible for mediating the anorectic actions of GDF15. Herein, we provide a brief overview of GDF15 biology with a focus on energy homeostasis, and highlight the implications of the recent receptor identification to this field and beyond. GDF15 is a hormone that is broadly expressed and is considered a biomarker the circulation of which positively correlates with the progression of many diseases. GDF15 administration leads to decreased food intake and body weight in obese rodents and nonhuman primates. GFRAL, a distant relative of receptors for a distinct class of the TGFβ superfamily ligands, has recently been identified as the high-affinity receptor binding and mediating the anorectic effects of GDF15. GDF15 and GFRAL are promising therapeutic targets for the treatment of disorders of energy homeostasis, including obesity and anorexia.