Though first introduced more than 130 years ago, the concept of stress diabetes or stress hyperglycemia has gained tremendous attention in recent years in view of the landmark article by van den Berghe and colleagues in 2001. As opposed to earlier work that suggested that hyperglycemia in the acute clinical setting may be beneficial, it now appears that lower glucose levels are associated with improved outcomes. The mechanisms behind the improved outcomes are numerous and seem to be tied to the inflammatory process. Both lower glucose values and insulin therapy seem to be anti-inflammatory, whereas hyperglycemia increases the proinflammatory process and negatively affects the innate immune system. Despite the numerous approaches to achieve normoglycemia described in the literature, only modest success has been achieved. Understanding the pathophysiology driving stress hyperglycemia--the stress response and modulation of the inflammatory process-seems to be the key to improving the care of the most critically ill and injured patients.