Gastroesophageal reflux disease (GERD) and laryngopharyngeal reflux (LPR) are sibling diseases that are a modern-day plague. Millions of Americans suffer from their sequelae, ranging from subtle annoyances to life-threatening illnesses such as asthma, sleep apnea, and cancer. Indeed, the recognized prevalence of GERD alone has increased threefold throughout the 1990s. Knowledge of the precise etiologies for GERD and LPR is becoming essential for proper treatment. This review focuses on the anatomical, physiological, neurobiological, and cellular aspects of these diseases. By definition, gastroesophageal reflux (GER) is the passage of gastric contents into the esophagus; when excessive and damaging to the esophageal mucosa, GERD results. Reflux that advances to the laryngopharynx and, subsequently, to other regions of the head and neck such as the larynx, oral cavity, nasopharynx, nasal cavity, paranasal sinuses, and even middle ear results in LPR. While GERD has long been identified as a source of esophageal disease, LPR has only recently been implicated in causing head and neck problems. Recent research has identified four anatomical/physiological “barriers” that serve as guardians to prevent the cranial incursion of reflux: the gastroesophageal junction, esophageal motor function and acid clearance, the upper esophageal sphincter, and pharyngeal and laryngeal mucosal resistance. Sequential failure of all four barriers is necessary to produce LPR. While it has become apparent that GER must precede both GERD and LPR, the head and neck distribution of the latter clearly separates these diseases as distinct entities warranting specialized focus and treatment. Anat Rec (Part B: New Anat) 289B:261–270, 2006. © 2006 Wiley-Liss, Inc.