This review examines the preclinical rationale for using glutamine supplements and reviews the prospective randomized trials using glutamine to improve outcomes in patients. A special role for glutamine in gut physiology and in management of a variety of serious illnesses has been suggested, because it is the most abundant extracellular amino acid, and is used at high rates by the gut, liver, central nervous system, and immune cells. A state of relative Gln deficiency has been postulated in humans based on the decrease in plasma Gln in acute critical illness, but the decrease in plasma Gln is not specific for that amino acid, predicts only poorer outcome, and has not been validated to identify a deficiency state. Current evidence does not necessarily predict a special need or role for Gln in critical illness. Clinical efficacy of supplemental Gln has been difficult to demonstrate, possibly related to the lack of a Gln deficiency state, the wide range of end points used that reflect the lack of certainty of the predicted effect of supplementation, the heterogeneous patient populations studied, the lack of stable clinical course during the study, the lack of adequate power, and the relatively short follow-up period. Prospective randomized clinical trials of Gln supplementation were reviewed in patients with short-bowel syndrome, during cancer chemotherapy and in bone marrow transplantation, and in surgical, burn, and intensive care unit patients. No firm recommendation can be made at this time. Future studies should seek to develop a more standard and stable design for intervention in sufficiently powered studies.