Mortality and morbidity of critically ill diabetic as well as nondiabetic patients are improved when blood glucose levels are tightly controlled to normoglycemia with intensive insulin therapy during their stay in the intensive care unit (ICU). This has been demonstrated in large prospective, randomized, controlled clinical studies for adult patients admitted to surgical and medical ICUs. Particularly for cardiac surgery patients, the hospital survival benefit with insulin therapy is most pronounced and maintained up to 4 years after hospital discharge, without inducing a substantial burden for the patients, their relatives, or society. Mechanistic studies exploring the molecular pathways involved suggest that intensive insulin therapy exerts its beneficial effects mainly through the maintenance of normal blood glucose levels.