Each of the macronutrients-carbohydrate, protein, and fat-has a unique set of properties that influences 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, thinking has progressed regarding the mechanisms by which each macronutrient may contribute to energy balance. At the beginning of this period, metabolic signals that initiated eating events (i.e., determined eating frequency) were emphasized. 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 (e.g., contribute to disordered eating). At this point, the predictive power of the macronutrients for energy intake remains limited.