Considerable clinical experience with proton pump inhibitors (PPIs) attests to their efficacy and safety in short-and long-term therapy for gastroesophageal reflux disease (GERD) in erosive esophagitis and endoscopy-negative (NERD) patients. One alternative to continuous PPI maintenance is PPI therapy administered noncontinuously (eg, "on demand"). Qualities of good PPI therapy for such a modality should include fast and sustained acid suppression. The newer-generation PPI esomeprazole has provided greater acid inhibition. Randomized controlled clinical trials comparing on-demand PPI versus placebo or versus continuous PPI therapy in GERD patients have shown that on-demand therapy with currently available PPIs (esomeprazole in particular) appears to be effective in the long-term management of patients with NERD or mild esophagitis and uninvestigated forms of GERD, who make up the overwhelming majority of patients with GERD. This is because it is safe and provides adequate symptom control and sustains quality of life. However, it is not indicated in patients with severe erosive esophagitis or with complicated esophagitis (ie, Barrett's esophagus or stricture). On-demand PPI therapy is important for economic reasons, as it may save up to two thirds of daily doses of the drugs, with a considerable containment of drug expenses. For a long-term disease whose treatment is aimed primarily at symptom control, it is a sensible and cost-effective approach.