The objectives of medical treatment of patients with gastroesophageal reflux disease (GERD) are relief of symptoms and healing of esophagitis, which can be achieved, at least in part, by drugs which suppress acid secretion. In patients with GERD symptoms and/or mild esophagitis, the best and most cost-effective therapeutic strategy is to start with a proton pump inhibitor with subsequent trial of step down of the intensity of therapy (e.g. H2-receptor antagonists). In patients with moderate or severe esophagitis, proton pump inhibitors are the mainstay of treatment and the most effective in preventing symptoms and esophagitis. In patients with mild disease, the recurrence of symptoms is less frequent and many patients may not need continuous maintenance therapy or may require treatment with either low dose proton pump inhibitors, H2-receptor antagonists or cisapride only. H. pylori eradication might be needed in GERD patients on long-term treatment with proton pump inhibitors, but the benefit of this strategy has not yet been adequately demonstrated. Antireflux surgery is a maintenance option for the young patient on long-term medical therapy. Improved medical therapy for GERD might depend on future agents with different therapeutic targets, including GABA inhibitors and nitric oxide modulating drugs in the control of the lower sphincter esophagus and in motility disorders, free radical scavengers in the prevention of mucosal damage and COX-2 specific inhibitors in the prevention of the progression of Barrets esophagus to adenocarcinoma. Finally, the modulation of some growth factors might have a potential role in delayed esophageal ulcer healing, refractory esophagitis and in Barretts esophagus.