Over the past decade knowledge relating to insulin’s action regulating glucose metabolism in vivo has expanded. It is now clear that physiologic increases in plasma insulin can potently inhibit glucose production by both direct and indirect means. Selective changes in insulin within the liver sinusoids (no change elsewhere in the body) are capable of setting glucose production between 0 (3 fold increase in insulin) and 7 (70% decrease in insulin) mg/kg-min. In addition insulin’s effects on muscle, fat, the alpha cell and the brain can also indirectly modify hepatic glucose output. A tripling of arterial insulin in the absence of a change in hepatic sinusoidal insulin inhibits glucose output from the liver by 50%. This effect appears to relate primarily to the action of insulin on adipose tissue. The role of physiological changes in insulin within the brain modifying glucose production remains controversial. Data in rodents support a role for neural insulin action while data in the dog and human do not. Regardless of the mechanisms involved in the indirect control of hepatic glucose production by insulin it is clear that in the normal animal the direct affect of insulin on the liver is dominant.