Proton pump inhibitors (PPIs) are antisecretory agents that are widely used in the short- and long-term management of gastroesophageal reflux disease (GERD) to relieve symptoms, heal esophagitis, and prevent complications, such as strictures and Barrett’s esophagus. The total healthcare costs of GERD are high, especially for maintenance treatment. Therefore, the choice of cost-effective therapeutic options is an ineluctable challenge for public health authorities, third-party payers, and patients. In some European Union countries, a recent trend of public health authorities is to promote the choice of less expensive PPIs, regardless of their antisecretory potency – this in spite of the evidence that newer PPIs provide superior symptom relief and esophageal erosion healing compared to earlier drugs. Several large clinical trials have demonstrated the superiority of esomeprazole over other PPIs at standard doses for both initial and continuous maintenance therapy in patients with moderate/severe erosive esophagitis. The non-erosive GERD poses a major challenge as this condition appears more frequently to be less responsive to PPIs. The use of PPIs with the strongest antisecretory properties might reveal to be more adequate and cost-effective, particularly for this indication.