OBJECTIVE Proton pump inhibitors remain the mainstay of medical therapy in gastroesophageal reflux disease. Despite their increasing use, up to 40% of patients are not fully satisfied with their antireflux therapy. Recent data on efficacy and safety are reviewed and causes of failure are discussed. RESULTS Several randomized studies and a metaanalysis have shown marginal differences in efficacy between various proton pump inhibitor regimens. In subgroups, however, such as severe esophagitis, esomeprazole may be superior. Poor compliance is one of the main causes of failure. Nonacid reflux is likely to play an important role, especially in patients with regurgitation or cough persisting on therapy. Genetic polymorphisms involved in proton pump inhibitor metabolism, Helicobacter pylori infection or nocturnal acid breakthrough during therapy are probably less important than initially suspected. Recent pharmacological developments include new proton pump inhibitor isomers, potassium competitive acid blockers and inhibitors of transient lower esophageal sphincter relaxations. CONCLUSIONS There are still important unmet needs in the treatment of gastroesophageal reflux disease. Optimizing acid control is unlikely to improve the condition of the majority of patients with incomplete proton pump inhibitor response. Inhibition of transient lower esophageal sphincter relaxations remains the major pharmacological target for future drug development.