An input-output schematization of plasma glucose homeostasis provides quantitative information on glucose fluxes and their control by insulin. Insulin action is dependent on the target tissue, the route of delivery, and the kinetics of insulin activation and deactivation, which are different for glucose production and disposal and are a function of insulin resistance. Under normal conditions, the closed-loop control of minute-by-minute insulin release by arterial glucose levels protects against both hyperglycemia and hypoglycemia. Open-loop insulin therapy faces the complexities of insulin pharmacokinetics and pharmacodynamics. Insulin therapy thus remains defiantly empiric.