Glutamine is a conditionally essential amino acid in the body because it falls into a shortage of supply during the catabolic state. Glutamine plays a key role in the gut function, immune system, and other essential processes in the body. A number of small randomized controlled trials have demonstrated positive clinical outcomes of a glutamine treatment, such as the ICU length of stay, and hospital mortality with glutamine supplementation. On the other hand, recent reports of large scale randomized controlled trials assessing the efficacy of glutamine supplementation demonstrated some negative effects and the main conclusions were a trend toward an increased 28-day mortality and significantly increased hospital stay and 6-month mortality in those who received glutamine. With such results, many academic societies have recommended that IV and enteral glutamine should not be used in a critical care setting based on the moderate quality of evidence available. The indiscriminate use of glutamine supplementation in critically ill patients with any type of organ failure can have deleterious effects. Nevertheless, more sophisticated and well-controlled larger studies will be needed to confirm how these moderate quality results are corrected and suggest the optimal usage of glutamine. More recent clinical trials have focused on specific populations and demonstrated benefits in burn and elective surgery patients with glutamine supplementation. The poor correlation between the plasma glutamine concentration and tissue concentration evoke scattered knowledge about glutamine treatments. A better understanding of the glutamine metabolism and proper guidelines for supplementation are expected.