PURPOSE OF REVIEW: This review will assess recent clinical and mechanistic data examining glutamine's ability to reduce morbidity and mortality in critical illness. RECENT FINDINGS: Updated metaanalysis data reveal a significant benefit of glutamine supplementation on mortality, length of stay, and infectious morbidity in critical illness. Recent data support glutamine's use in critically ill patients requiring parenteral nutrition and new data reveal safety and efficacy in head-injured patients. Further, new findings on glutamine's beneficial effect on insulin resistance in critical illness will be reviewed. Recent laboratory data have clarified a number of key mechanistic pathways by which glutamine may improve outcome in critical illness. SUMMARY: Severe glutamine deficiencies occur rapidly in critical illness. The magnitude of glutamine deficiency is correlated with ICU mortality. Further, metaanalysis reveals glutamine reduces morbidity and mortality in critical illness. It is likely that our new understanding of the molecular pathways by which glutamine acts will lead to insight on how best to utilize glutamine as a nutritional therapy. Presently, randomized, multicenter clinical trials utilizing glutamine as both nutritional replacement and pharmacologic intervention, independent of nutritional needs, are ongoing.