The homeostatic regulation of adiposity is a physiological concept that originated nearly 70 years ago, the genetic foundations of which have just begun to emerge. A key element of this concept is the existence of one or more humoral mediators, which circulate at levels that reflect body fat stores and which signal through neuronal receptors to elicit appropriate behavioural and metabolic responses over short time periods. Initial insights into adiposity regulation came from the positional cloning of mouse obesity mutations, but the field is now poised to address specific physiological questions using more sophisticated genetic approaches.