Endoscopic-negative reflux disease (ENRD) is the most common presentation of gastro-oesophageal reflux disease (GERD)-affecting up to 70% of these individuals. In the last three decades therapeutic studies have focused solely on the treatment of patients with erosive oesophagitis. However, more recent studies have shifted our attention to defining, understanding and treating those with ENRD. GERD has traditionally been approached as a spectrum with ENRD at the mild end and complicated GERD (i.e. patients with erosive oesophagitis, stricture and Barrett's oesophagus) being at the other end, suggesting that patients' disease may progress over time along the spectrum. Current data indicate that ENRD should be approached as a unique entity rather than a part of the GERD spectrum and that over time only a few patients with ENRD will develop GERD-related complications. Patients with ENRD are a heterogenous group of patients with different aetiologies for their heartburn symptoms, including motor events, reflux of acidic or nonacidic gastric contents, minute changes in intraesophageal pH (pH < 4), mucosal hypersensitivity, and emotional or psychological abnormalities. By dropping the spectrum concept, which emphasizes oesophageal mucosal injury, we can focus our attention on the specific mechanisms that lead to symptom generation in each of the three unique groups of GERD (ENRD, erosive oesophagitis and Barrett's oesophagus) and on the specific therapeutic modalities that benefit each of these individual groups. Acid suppressive therapy with proton pump inhibitors is highly effective in healing erosions and controlling symptoms in those with erosive oesophagitis. In those with ENRD the resolution or control of heartburn with proton pump inhibitor therapy is greater than that with placebo or H2 receptor antagonist, but not as consistent nor as impressive as the results observed in studies of patients with erosive oesophagitis. By considering the mechanisms involved in ENRD symptom generation, future studies that include high-dose proton pump inhibitors, promotility agents (alone or in combination with proton pump inhibitors), transient lower oesophageal sphincter reducers, or pain modulators (e.g. tricyclic antidepressant agents) may prove beneficial.