Abstract The ability to respond to variations in nutritional status depends on regulatory systems that monitor nutrient intake and adaptively alter metabolism and feeding behavior during nutrient restriction. There is ample evidence that the restriction of water, sodium, or energy intake triggers adaptive responses that conserve existing nutrient stores and promote the ingestion of the missing nutrient, and that these homeostatic responses are mediated, at least in part, by nutritionally regulated hormones acting within the brain. This review highlights recent research that suggests that the metabolic hormone fibroblast growth factor 21 (FGF21) acts on the brain to homeostatically alter macronutrient preference. Circulating FGF21 levels are robustly increased by diets that are high in carbohydrate but low in protein, and exogenous FGF21 treatment reduces the consumption of sweet foods and alcohol while alternatively increasing the consumption of protein. In addition, while control mice adaptively shift macronutrient preference and increase protein intake in response to dietary protein restriction, mice that lack either FGF21 or FGF21 signaling in the brain fail to exhibit this homeostatic response. FGF21 therefore mediates a unique physiological niche, coordinating adaptive shifts in macronutrient preference that serve to maintain protein intake in the face of dietary protein restriction.