<p>The melanocortin system is fundamental for the regulation of whole-body energy homeostasis. This system consists of pro-opiomelanocortin (POMC) and agouti-related peptide (AgRP) neurons in the arcuate nucleus of the hypothalamus (ARH), as well as downstream neurons expressing melanocortin receptors (MCRs) located in various brain regions. Emerging evidence highlights significant anatomical and functional sex differences within the melanocortin system, influencing sex-dimorphic metabolic adaptations, the regulation of appetite and energy expenditure and susceptibility to metabolic conditions. These differences are primarily shaped by sex hormones, genetic and environmental factors as well as distinct neurocircuitry organization between males and females. These sex-specific regulatory mechanisms have important implications for the pathophysiology of metabolic disorders, including obesity, type 2 diabetes, and eating disorders. In this review, we explore current knowledge on sex differences in the development and function of the melanocortin system and how this is translated into sex-dimorphic control of metabolism. This emphasizes the need to incorporate sex as a critical variable in both metabolic research and clinical studies. Understanding these mechanisms may provide more precise and effective therapeutic strategies for metabolic disorders, obesity, and appetite dysregulation in both sexes.</p>