Stress hyperglycaemia is a distinctive clinical feature of critical illness. Stress mediators, namely stress hormones, cytokines and the central nervous system, interfere with normal carbohydrate metabolism, especially in the liver and skeletal muscle. Central insulin resistance, defined as increased hepatic gluconeogenesis and glucose output despite abundant endogenous insulin levels, appears pivotal to the occurrence of stress hyperglycaemia. The skeletal muscle is refractory to insulin action too. Peripheral insulin resistance is predominantly attributed to inhibition of the skeletal muscle glycogen synthesis. Significantly increased noninsulin-mediated glucose transport into the skeletal muscle overrules defective insulin-mediated glucose transport. Inflammatory mediators and counter-regulatory hormones have been shown to impede crucial elements of the insulin-signalling pathway (insulin receptor substrates/IRS-1/phosphatidylinositol 3-kinase/Akt/Glucose Transporter 4). Still, exogenous insulin administration normalises blood glucose levels in this setting. Insulin treatment may counteract hepatic insulin resistance during acute critical illness. During prolonged critical illness, therapeutic insulin effects seem mediated by increased skeletal muscle glucose uptake and use.