Alterations in glucose metabolism, including hyperglycemia associated with insulin resistance, occur in critical illness. Acutely, such alterations result from normal, adaptive activation of endocrine responses, including increased release of catecholamines, cortisol, and glucagon and a reduced glucose uptake capacity. In prolonged critical illness, neuroendocrine changes lead to more extensive metabolic changes that may be associated with development of complications and poor prognosis. Until recently, hyperglycemia was not routinely controlled in intensive care units, except among patients with known diabetes mellitus. Studies have demonstrated that glycemic management in postmyocardial infarction in patients with diabetes is an effective practice. Recent investigation has extended this to demonstrate reduced morbidity and mortality in a surgical critically ill population with and without diabetes mellitus in later phases of critical illness. Although the mechanisms for improved patient outcomes need to be established, this novel approach to management of hyperglycemia in critical illness is a new and important concept for those working in critical care. This article reviews alterations in glucose metabolism which occur in critically ill patients and discusses potential mechanisms and mediators (e.g., hormones, cytokines) that may play a key role in hyperglycemia and insulin resistance during acute and prolonged phases of severe illness. The article addresses the application of insulin protocols and exogenous regulation of glucose concentration in critical illness based on a review of recent intervention studies.