Hyperglycemia and insulin resistance often occur following injury and/or critical illness. Whereas intensive insulin treatment reduces hyperglycemia, mortality and morbidity in certain patients, little is known regarding the pathophysiology of acute insulin resistance following injury and infection. Studies suggest that acute insulin resistance is complex and might differ in a tissue-specific manner, involving multiple causative factors and intracellular signaling pathways. Therefore, the advantages of intensive insulin therapy might not be uniform to all injuries or critical illnesses. Clearly, the increased incidence of hypoglycemic incidents following intensive insulin therapy indicates a need for understanding the underlying molecular mechanisms of the acute development of insulin resistance, which will allow a more targeted approach to treat altered glucose metabolism of critically ill patients. © 2009 Elsevier Ltd. All rights reserved.