Medical management of gastroesophageal reflux disease (GERD) includes lifestyle modifications and pharmacological interventions. Weight loss is recommended for obese and overweight subjects; avoidance of meals and alcoholic beverages before sleeping, as well as recumbency on the left side and with the bed head elevated may prove useful. Currently, proton-pump inhibitors (PPIs) represent the mainstay of medical treatment given their outstanding efficacy in relieving heartburn, the cardinal symptom of GERD, as well as in healing reflux esophagitis. Given the modest diagnostic sensitivity of endoscopy and the costs of pH/pH-impedance monitoring, in the absence of alarm symptoms, a 4–8 week PPI trial resulting in relief of reflux symptoms allows a presumptive diagnosis of GERD in clinical practice. Long-term maintenance PPI therapy is effective and safe: it is strongly recommended for patients with severe reflux esophagitis and Barrett’s esophagus and is conditionally indicated for mild reflux esophagitis and non-erosive GERD as documented by pH/pH-impedance monitoring. Some patients with documented GERD do not achieve symptom remission even with high-dose PPIs: on-PPI pH-impedance monitoring is warranted for establishing a direct link between symptoms and reflux, and can guide the choice between available add-on and alternative medical therapies in PPI-refractory GERD.