A recent editorial in Critical Care Medicine was titled “Glutamine, a life-saving nutrient, but why?” (2003; 31:2555–2556). This review will attempt to utilize new understanding of gene–nutrient interactions and molecular medicine to address potential mechanisms by which glutamine may be lifesaving after critical illness and injury. Recent meta-analysis data reveal that glutamine seems to exert a beneficial effect on mortality in critically ill patients. However, this effect seems to be dose and route dependent. The questions that remain to be answered are in what settings and via what method of administration does this phamaconutrient show optimal benefit? It is likely that examination of the molecular mechanisms by which glutamine exerts its effects will lead to an understanding of how best to utilize glutamine as both a pharmacologic and a nutritional agent. Clearly, clinical critical illness leads to a marked deficiency in glutamine that is correlated with mortality in the intensive care unit setting. It makes obvious sense that the deficiency of this vital stress nutrient should be replaced. In addition, recent laboratory data reveal glutamine may act via mechanisms independent of its role as a metabolic fuel. These include enhanced stress protein response, attenuation of the inflammatory response, improved tissue metabolic function, and attenuation of oxidant stress. Present data indicate that glutamine functions as a metabolic fuel and “stress-signaling molecule” after illness and injury. Thus, deficiencies observed in critical illness demand replacement for both pharmacologic and metabolic optimization. Presently, randomized, multicenter, clinical trials utilizing glutamine as a pharmacologic and a nutritional agent are ongoing.