The human body is programmed to maintain constant homeostasis of all body systems through a complex neuroendocrine and autonomic network. Critical illness alters this homeostasis through various exaggerated autonomic and cytokine responses. The mechanisms that are impaired include glucose cellular transport and peripheral and hepatic insulin uptake. Over the past decade, numerous reports have described the deleterious effects of hyperglycemia. In 2001, in a randomized prospective study of critically ill patients, Van den Berghe [1] first reported that intensive glucose control (110 mg/dL) significantly decreased morbidity and mortality. This study was a catalyst for a multitude of subsequent reports evaluating the effects of glycemic control in other patient populations. This article first describes the pathophysiology of hyperglycemia in critical illness, and then summarizes the recent literature on the benefits of decreasing glucose levels and potential harmful effects of hypoglycemia (Table 1).