The gut is an important organ, which not only digests and absorbs food but selectively excludes bacteria and toxins from entering the body. It has one of the highest rates of protein turnover of any tissue in the body. Maintenance of epithelial cell proliferation and secretory, digestive, and gut-associated lymphatic tissues (GALT) function requires a constant supply of substrates. A primary feature of the metabolic response to fasting, accidental injury, or surgery is accelerated skeletal muscle proteolysis and translocation of amino acids from the periphery to visceral organs. Nevertheless, the serosal supply of nutrients may be inadequate to maintain normal gut barrier function. The following factors influencing gut nutrient requirements and the effect of the gut on the whole-body metabolism are discussed: (i) diet composition and gut mass, (ii) physiological and pathologic nutrient requirements of epithelial and GALT cells, (iii) route of nutrition (enteral versus parenteral), and (iv) nutrient inadequency and gut barrier dysfunction (structural or immune mediated).