Almost twenty years after the discovery of ghrelin, a potent Growth Hormone Secretagogue (GHS) and orexigenic peptide synthesized in the stomach and acting on its cognate receptor, the GHSR, LEAP2 (Liver-Expressed Antimicrobial Peptide 2), produced mainly in the liver and small intestine, was identified as an endogenous ghrelin antagonist. This article reviews the initial characterization of LEAP2 as an antimicrobial peptide and its role in opposing ghrelin’s actions on food intake, GH secretion, hedonic feeding and energy homeostasis. We also describe the long-term regulation of ghrelin and LEAP2 by positive and negative energy balance, and their short-term regulation by meals and nutrient intake. We then discuss the effect of LEAP2 variants on the concentration and function of LEAP2 and their possible associations with altered eating behaviors. Finally, the potential implications of LEAP2 in obesity or pathologies associated with abnormal feeding behavior such as anorexia nervosa are also highlighted. Due to their opposite actions on food intake, energy homeostasis, glucose homeostasis, hedonic feeding and reward, ghrelin and LEAP2 represent key pharmacological targets for disorders impacting energy homeostasis and eating. These discoveries open up new perspectives for the understanding of the mechanisms that regulate eating behaviors and more broadly energy balance, relayed by the GHSR, in physiological and pathological conditions.