Transient relaxations of the lower esophageal sphincter (tLESRs), but not delayed gastric emptying, are major mechanisms of gastroesophageal reflux in premature infants. These findings are similar to those seen in older children and adults with gastroesophageal reflux disease. Newer antireflux therapies should be developed that target the reduction of gastric acidity or reduction in the number of tLESRs.