Python intestine responds rapidly to luminal nutrients by increasing mass and upregulating nutrient transport. Candidates for luminal signals triggering those responses include mechanical stimulation, single or several dietary nutrients, and endogenous secretions. To identify signals, we infused into the python's small intestine either a nonnutrient solution (saline) or a single- or multinutrient solution. Python intestine failed to respond trophically or functionally to luminal infusions of saline, glucose, lipid, or bile. Infusion of amino acids and peptides, with or without glucose, induced an intermediate response. Infusion of nutritionally complete liquid formula or natural diet induced full intestinal response. Intact meals triggered full intestinal responses without pancreatic or biliary secretions, whereas direct cephalic and gastric stimulation failed to elicit any response. Hence neither physical stimulation (cephalic, gastric, or intestinal) nor the luminal presence of glucose, lipids, or bile can induce intestinal response; instead, a combination of nutrients is required (even without pancreaticobiliary secretions), the most important being amino acids and peptides. This is understandable because pythons, as carnivores, have a high-protein diet.