Recent work emphasizes the critical role played by the mucosa in a number of nutritionally important biosyntheses. This literature raises important questions regarding conditionally essential amino acid nutrition in intestinal disease. Further, it is becoming clear that from a metabolic perspective enteral and systemic amino acids may suffer radically different fates in the mucosal enterocyte. It is unclear, however, whether the effects of glutamine, generally accepted as beneficial, reflect its role in mucosal energetics, as often implied in the literature, or whether glutamine has more specific effects. On the other hand, although butyrate is an important potential fuel for the mucosal cells, it plays a more complex and specific role in the regulation of proliferative activity and differentiation in normal and neoplastic enterocytes. The mechanisms underlying the trophic effects of nucleotides remain obscure, but in our opinion do not reflect their role as potential precursors for nucleic acid synthesis. Recent advances in isotopic techniques now allow the complex metabolic issues to be addressed, and our increasing understanding of gene regulation in the intestinal mucosa should allow the unequivocal identification of specific effectors at the molecular level.