Fibroblast growth factor 21 (FGF21) is a liver-derived hormone with pleiotropic metabolic effects. Its production is induced by various dietary imbalances in mice (including low-protein and ketogenic diets, fructose feeding and ethanol), hinting that it might influence food preference given the role of the liver in maintaining homeostatic levels of circulating nutrients. In 2016, it was shown that FGF21 selectively inhibits consumption of sugars and the primary product of their fermentation, ethanol, but not intake of fat, protein or complex carbohydrates. Since then, studies have sought to unravel this selectivity, its physiological purpose and translational relevance, as well as delineate the neural mechanisms involved. Initially found to impact ingestive behaviours in mice and non-human primates, FGF21 is also induced in humans by sugars and, far more dramatically, by acute alcohol intake. Genetic studies have revealed that patterns of weekly candy and alcohol consumption are associated with genetic variants in FGF21 and its co-receptor β-klotho (KLB), suggesting that liking for sugar, and fermented sugar, may be influenced by natural variation in FGF21 signal strength in humans. Herein, we discuss our nascent understanding of FGF21 as a selective negative regulator of sugar and alcohol appetite as well as reasons why such a peculiar system may have evolved in mammals. Uncovering the regulatory network governing sugar, and fermented sugar, intake could provide new opportunities to improve dietary choices in a population suffering from Western diet-induced diseases fuelled in part by a runaway sweet - and alcohol - tooth.