Since the pioneering work of Windmueller and Spaeth, the importance of glutamine to the support of intestinal mucosal metabolic function has become generally accepted. Nevertheless, the mechanisms underlying this role still remain obscure. This paper explores a number of questions: 1) Is glutamine essential for intestinal function? 2) To what extent does this relate to its intermediary metabolism? 3) What is the importance of glutamine as a biosynthetic precursor? 4) Is glutamine supplementation of the nutrient mixture presented to patients of any metabolic or clinical benefit? As a result of this exploratory exercise, the following general conclusions were reached: 1) Much suggestive biochemical and physiologic evidence exists that implies that glutamine, especially systemic glutamine, supports the function of the intestinal mucosal system. 2) Despite the extensive metabolism of this amino acid by the intestinal tissues, most evidence suggests that if glutamine does play a physiologic role in the bowel, it is not compellingly related to its intermediary metabolism. 3) There is, on the other hand, evidence that the mucosal cells not only utilize extracellular glutamine but synthesize the amino acid. Given that inhibition of glutamine synthesis inhibits both proliferation and differentiation of mucosal cell cultures, this suggests some more subtle regulatory role. This notion is supported by the demonstration that glutamine will activate a number of genes associated with cell cycle progression in the mucosa. 4) Despite the accumulated evidence, the mechanisms underlying glutamine's function and the question whether glutamine supplementation uniformly benefits mucosal health remain equivocal at best.