Similar to adults, children under physiologic stress can develop an imbalance in defensive (mucosal layer, motility) and aggressive (gastric acid, bile salts, enzymes) factors responsible for maintaining a healthy gastrointestinal tract. Hypoxia in the gastrointestinal tract likely disrupts the defensive factors, thereby permitting damage by aggressive factors to upper gastrointestinal epithelium that may progress to stress ulceration and acute upper gastrointestinal tract bleeding (UGIB). The basic pathophysiology may be similar in children and adults; however, differences in the time to developing ulceration, ulcer location, and number of ulcers have been reported. Functional development of the gastrointestinal tract is influenced by disease, gestational and postnatal age, and exposure to and type of enteral feedings, thereby confounding the development and prophylaxis of UGIB in neonates and infants. In addition, pharmacotherapy decisions are often complicated by drug administration issues and adverse effects.