Gastroesophageal reflux disease (GERD) is a very prevalent condition and has a high impact on the quality of life. Nevertheless, pathophysiology is complex and multi-factorial. Several mechanisms have been proposed: decreased salivation, decreased lower esophageal sphincter pressure resting tone, presence of hiatal hernia, increased number of transient lower esophageal sphincter relaxations, increased acid, and pepsin secretion, duodeno-gastro-esophageal reflux of bile acids and trypsin. Other factors contributing to the pathophysiology of GERD include poor esophageal clearance, delayed gastric emptying and impaired mucosal defensive factors. Esophageal mucosa integrity is impaired both in patients with erosive esophagitis also in regions macroscopically normal and in NERD patients. Patients with functional heartburn have instead a normal mucosal integrity. The mechanisms underlying extra-esophageal GERD are instead more controversial. Reflux symptoms could be caused by esophageal hypersensitivity as a result of visceral neural pathway dysfunction. Multiple mechanisms influence the perception of GERD symptoms, such as the acidity of the refluxate, its proximal extent, the presence of gas in the refluxate, duodeno-gastro-esophageal reflux, mucosal integrity, and peripheral and central sensitization. Furthermore several risk factors can influence the onset of GERD and its complications such as life style, obesity, genetics, pregnancy, and stress. In particular obesity is associated with complications related to longstanding reflux such as erosive esophagitis, Barrett's esophagus, and esophageal adenocarcinoma. Understanding the pathophysiology of gastro-esophageal reflux is important for future targets for therapy. Further research is necessary to improve the current knowledge of the contributing factors leading to GERD.