Gastroesophageal reflux disease (GERD) is caused by a combination of esophageal motor dysfunction accompanied by maintained gastric acid secretion. Noninvasive medical treatment of GERD is mainly provided by inhibiting gastric acid secretion, because this is easier than restoring esophageal motor function by administration of drugs. Proton pump inhibitors (PPIs) and histamine H2 receptor antagonists (H2RAs) are two major acid-suppressing drugs used for the treatment of GERD. PPIs have better characteristics for the long-term treatment of GERD, because they have a long-lasting, strong effect of raising intragastric pH and have no tachyphylaxis/tolerance phenomena on repeated dosing. Some patients with Helicobacter pylori-negative high-grade GERD may show nocturnal decreases in pH during treatment with PPIs and resistance to treatment with PPI. For these patients, addition of H2RAs to PPIs can be useful for controlling GERD, at least for short-term treatment. For long-term control of such cases, further studies are necessary.