Gastroesophageal reflux disease (GERD) is a common condition that has a substantial impact on quality of life in patients and is a leading risk factor for esophageal adenocarcinoma. Now therapy with proton pump inhibitors (PPIs) is a basic method in the treatment of patients with GERD; however, one third of the patients do not respond to the therapy used. The causes of refractory GERD are a fairly large group of heterogeneous factors contributing to the inefficacy of PPIs in adequate dosage. Among these factors, there is low compliance by patients to the prescribed treatment regimen; nocturnal acid breakthrough; CYP2C19 gene polymorphism; chiasm syndrome with functional diseases of the gastrointestinal tract; non-acidic refluxes in a patient; thoracic esophageal motility disorders; the increased number and duration of transient lower esophageal sphincter relaxation periods; hiatus hernia; and misdiagnosis. 24-hour pH impedance and high-resolution esophageal manometry are now the most informative diagnostic techniques in patients who fail to respond to PPI therapy. These techniques allow one to timely recognize the causes of refractory GERD, to make a differential diagnosis with other nosological entities, and to timely correct therapy for each individual patient.