Research into new methods of controlling acid secretion is driven by existing medical needs in gastro-oesophageal reflux disease treatment. Histamine receptor subtype 3 agonists offer one approach for acid inhibition but no agent is yet undergoing clinical testing. Other, as yet unrealised strategies include preventing the fusion of the tubulovesicular elements that contain H⁺/K⁺-ATPase with the parietal cell membrane, or blocking channels that recycle K⁺ in the parietal cell. Of more promise are gastrin (cholecystokinin) receptor antagonists and potassium-competitive acid blockers; examples of both are in clinical development. It is probable that gastrin receptor antagonists would be used adjunctively with proton pump inhibitors, possibly for meal-induced reflux. The potassium-competitive acid blockers have attributes that may facilitate use as monotherapy for the treatment of gastro--oesophageal reflux disease. The early promise of gastrin receptor antagonists and potassium-competitive acid blockers remains to be defined in large-scale trials.