The liver plays a unique role in nutrient homeostasis. Its anatomical location makes it ideally suited to control the systemic supply of absorbed nutrients, and it is the primary organ that can both consume and produce substantial amounts of glucose. Moreover, it is the site of a substantial fraction (about 25 %) of the body's protein synthesis, and the liver and other organs of the splanchnic bed play an important role in sparing dietary N by storing ingested amino acids. This hepatic anabolism is under the control of hormonal and nutritional changes that occur during food intake. In particular, the route of nutrient delivery, i.e. oral (or intraportal) v. peripheral venous, appears to impact upon the disposition of the macronutrients and also to affect both hepatic and whole-body nutrient metabolism. Intraportal glucose delivery significantly enhances net hepatic glucose uptake, compared with glucose infusion via a peripheral vein. On the other hand, concomitant intraportal infusion of both glucose and gluconeogenic amino acids significantly decreases net hepatic glucose uptake, compared with infusion of the same mass of glucose by itself. Delivery of amino acids via the portal vein may enhance their hepatic uptake, however. Elevation of circulating lipids under postprandial conditions appears to impair both hepatic and whole-body glucose disposal. Thus, the liver's role in nutrient disposal and metabolism is highly responsive to the route of nutrient delivery, and this is an important consideration in planning nutrition support and optimising anabolism in vulnerable patients.