Despite the traditional approach of thinking of energy and protein as two separate entities when balancing dairy rations, the response of the cow to increased supply of nutrients often crosses these artificial compartments. For example, supplementation of protein as casein infusions increases not only protein yield but also milk and lactose yields. As part of the quest to enhance the biological and economic efficiency of the cow, we need to understand how and where such interactions occur. The response in lactose yield to protein supplementation is almost identical (g/g) to the response in protein yield. An obvious candidate for the link between lactose output and protein supply is glucose, as increasing protein supply through casein infusion increases the whole body (WB) rate of appearance (Ra) of glucose (sum of real portal absorption, gluconeogenesis and glycogenolysis). In ruminants, utilization of arterial glucose by the portal-drained viscera averages 22% of WB glucose utilization and real portal absorption contributes, on average for 14% of WB Ra glucose, with variations from 0 to 37%, in relation with starch digested in the intestine. Most of the remainder of WB Ra originates from gluconeogenesis, with a liver contribution of at least 85% and the kidneys contribution at most 15% to non-detectable levels in animals fed a concentrate diet. Infusion of casein did not alter real portal absorption of glucose and neither did it decrease portal-drained viscera utilization of arterial glucose. Indeed, in one study where measured simultaneously, the increased WB Ra of glucose induced by post-ruminal casein infusion originated from an increment in liver net flux. In dairy cows, the efficiency of WB transfer of the carbons of casein into glucose is on average higher than the maximal theoretical synthesis of glucose from protein supplementation, once the increment in milk protein yield is taken into account. Stimulation of utilization of other glucose precursors or recycling of glucose could explain this high efficiency. Despite a strong relationship between casein supply, WB Ra of glucose and lactose yield, increased WB Ra of glucose does not seem to be the driving force stimulating lactose yield. Increased lactose yield is only observed when the increment in WB Ra of glucose is due to increased protein supply; the same relationship does not exist when glucose Ra is increased through energy supply. It may be that some of the essential AA are playing a key role in some metabolic pathways or are simply stimulating protein synthesis. The latter hypothesis might result in increased milk protein synthesis, 'pulling' lactose synthesis due to its osmotic role, or in stimulating 'enzyme machinery' involved in gluconeogenesis, milk protein and/or lactose synthesis. Overall, this 'simple' example demonstrates the intricate integration between protein and energy metabolism.