Human milk is a highly complex fluid with a nutrient balance and an array of functional properties that may promote a level of metabolic efficiency that is not attainable when a cow milk-based formula is fed. This is not a novel idea. Mitchell in 1933 proposed that the level of efficiency of energy use is determined by the nutrient "balance" in the diet. Nonetheless, difficulties remain in the attempt to reconcile the low levels of intake with established estimates of energy needs. If the amount of energy that appears necessary for growth and maintenance of a 4-month-old infant is compared with that from his or her intake of an exclusive human milk diet, the infant should have little or no energy left for activity. Do metabolic economies contribute to more efficient uses of energy for growth and maintenance in breastfed infants? Are there differences in body composition? Does more efficient use of energy occur as a result of a decrease in clinical and subclinical infections? Is efficient energy utilization accomplished by significant curtailment in activity? If an excess level of energy is consumed by bottlefed infants, what are the positive or negative short-term or long-term consequences? These questions are the focus of research in numerous laboratories. Field and clinical studies of breastfed infants and in vitro studies of human milk offer unique opportunities to understand basic mechanisms of human adaptations to nutrient intake and environmental challenges.