<p>The response to infection is an energy-demanding process that bolsters cell division and protein synthesis to overcome a rapidly dividing and invasive pathogen. Paradoxically, anorexia, a conserved behavioural response to infection, sharply limits food intake during this period of high energy demand. Leptin, the&#xa0;release of which from adipocytes is coordinated with the immune response, signals to the hypothalamus to balance energy availability and expenditure with respect to various physiological processes. Congenital deficiency of leptin or its receptor in humans predisposes to infection. Moreover, low serum levels of leptin are associated with poor outcomes in sepsis. Leptin activates pro-opiomelanocortin neurons, which produce melanocortins, a family of peptide hormones that has diverse roles. The melanocortins have targets in many organ systems and their functions include suppressing inflammation and upregulating sympathetic tone. Here, we discuss what is known about leptin and melanocortin signalling in the response to infection, with evidence from preclinical research and human studies. We close by offering insights into how study of these pathways might be translated into therapies for infectious disease as well as new avenues for exploration.</p>