Gastroesophageal reflux disease (GERD) is a chronic common disorder for which patients often refer to specialists. In the last decades, numerous studies helped to clarify the pathophysiology and the natural history of this disease. Currently, in the clinical setting, GERD is defined by the presence of symptoms that, when endoscopic investigation is required, permit to distinguish between cases with or without associated esophageal mucosal injuries. These conditions are called erosive reflux disease and non-erosive reflux disease (NERD), respectively. The latter is the most common manifestation of GERD. Symptoms are defined typical, as heartburn and regurgitation, and atypical (also called extra-esophageal), as coughing and/or wheezing, hoarseness, sore throat, otitis media, and dental manifestations. In this context, it is crucial for clinicians to investigate the presence of features of suspected malignancy, as unexplained weight loss, anemia, dysphagia, persistent vomiting, familiar history of cancer, long history of GERD, and beginning of GERD symptoms after the age of 50 years. The presence of these risk factors should induce to perform an endoscopic examination. Particular attention should be given to functional conditions that can mimic GERD, such as functional heartburn and hypersensitive esophagus as well as, more rarely, eosinophilic esophagitis. The former ones have different pathophysiology and this explains the frequent non-response to proton pump inhibitor drugs. This narrative review provides to clinicians a useful and practical overview of the state-of-the-art on advancements in the knowledge of GERD.