In the course of mammalian development milk has evolved with unique characteristics as has the capacity of the neonatal rat to process this nutrient source. The primary carbon source in milk is fat, which provides two readily utilized metabolites, acetoacetate and D(-)-3-hydroxybutyrate (ketone bodies), as well as free fatty acids and glycerol. Carbohydrate provides less than 12% of the caloric content of rat milk and glucose has to be produced by the suckling rat to maintain glucose homeostasis. One would predict that glucose would be used sparingly and in pathways that cannot be satisfied by other readily available metabolites. Studies of the uptake of metabolites and the development of key enzymes for the utilization of glucose and ketone bodies by developing brain support the concept that ketone bodies are preferred substrates for the supply of carbon to respiration and lipogenesis. Astrocytes, oligodendrocytes, and neurons from developing brain all have an excellent capacity to use ketone bodies for respiration. By contrast, glucose is utilized preferentially in the hexose monophosphate shunt by all three cell populations. We are examining the requirement for ketone bodies by developing brain with the application of a system to rear rat pups artificially on a milk substitute that promotes a hypoketonemia.