The liver plays a central role in the control of glucose production. It is also involved in the regulation of insulin secretion and sensitivity through neural pathways. This review will address recent developments in the mechanisms by which hepatic metabolism affects glucose homeostasis in health and disease. Oral glucose feeding elicits several systemic and hepatic alterations of intermediary metabolism through the activation of neural pathways. How this may affect glucose metabolism will be briefly discussed, and alterations of glucose homeostasis in liver disease will be briefly described. There is evidence that a portion of intrahepatic glucose can be converted into lipids in the process of de-novo lipogenesis. How this may be involved in the control of glycaemia and lipid concentrations will be reviewed. Finally, molecular mechanisms by which the alteration of liver metabolism may affect systemic glucose homeostasis will be outlined.