Despite acid secretion being normal in the majority of patients with gastro-esophageal reflux disease (GERD) or Barrett’s esophagus, acid inhibition represents the mainstay of treatment for both these conditions, with the aim of reducing the aggressive nature of the refluxate toward the esophageal mucosa. Proton pump inhibitors (PPIs) represent, therefore, the first choice medical treatment for GERD, in that they are able to provide an 80–85% healing rate for esophageal lesions, a 56–76% symptom relief and also reduce the incidence of complications, such as strictures as well as dysplasia and adenocarcinoma in Barrett’s esophagus. According to a widely quoted systematic review, compared to patients with erosive esophagitis, patients with non-erosive reflux disease (i.e., NERD) display a reduced symptom relief with PPIs, with about 20% reduction of therapeutic gain. In this issue of NeuroGastroenterology & Motility, Weijenborg et al. address for the first time the PPI efficacy in subpopulations of patients with NERD. The study shows clearly that, when the diagnosis is accurately made by including a functional test, NERD patients respond to PPI therapy in a similar way to those with erosive disease. Although not as frequent as previously suggested, however, PPI-refractory heartburn does exist. Some 20% (range: 15–27%) of correctly diagnosed and appropriately treated patients do not respond to PPI treatment at standard doses. Although the pathophysiology underlying PPI failure in GERD is complex and likely multifactorial, acid (be it the sole component of refluxate or not) still remains a major causative factor. A better and more predictable form of acid suppression should therefore be pursued.