Concepts for the control of food intake and the idea of regulation of body weight have been proposed for well over 50 years. The debate has been based mainly on animal experiments often using brain interventions. Based on animal and in vitro molecular studies, changes to circulating 261leptin concentrations are thought to alter the hypothalamic expression of anorexigenic and orexigenic neuropeptide effector molecules, which promote corrective responses in energy intake (EI) and expenditure to minimize perturbation to energy balance. It has also been suggested that day-to-day food intake is regulated via nutrient-specific appetite control mechanisms rather than an energy-based regulatory system reliant on the energy content of the diet. Recent findings suggesting that fat-free mass (FFM) and resting metabolic rate (RMR) play important roles in day-to-day food intake suggest that the classic adipocentric model of appetite control could easily be revised to reflect the influence of RMR and energy demands.