Each of the macronutrients, carbohydrate, protein and fat, has a unique set of properties that influence health, but all are a source of energy. The optimal balance of their contribution to the diet has been a long-standing matter of debate. Over the past half century, there has been a progression of thinking regarding the mechanisms by which each may contribute to energy balance. At the beginning of this time period, the emphasis was on metabolic signals that initiated eating events (i.e., determined eating frequency). This was followed by an orientation to gut endocrine signals that purportedly modulate the size of eating events (i.e., determined portion size). Most recently, research attention has been directed to the brain where the reward signals elicited by the macronutrients are viewed as potentially problematic (i.e., contribute to disordered eating). At this point the predictive power of the macronutrients for energy intake remains limited.