Gastroesophageal reflux disease (GERD) is one of the most common gastrointestinal disorders, and the pharmacological management of GERD is a topic of intense interest given the sizeable yearly expenditure for antireflux therapies. GERD is primarily a motor disorder of the esophagus, yet pharmacological approaches directed at altering esophageal motility have been only partially effective. Antisecretory therapy is the mainstay of treatment for GERD. Both H2 receptor antagonists (H2RA) and proton pump inhibitors (PPIs) are effective in the treatment of GERD, but PPI therapy is clearly superior in the treatment of severe disease and in the healing of erosive esophagitis. A treatment schema for GERD based on presenting symptoms is outlined, promoting a stepwise approach to the appropriate use of antisecretory therapy.