With patients referring symptoms of gastro-esophageal reflux disease (GERD), 2 initial approaches should be considered: an empiric therapy (treat and test strategy) or a strategy based on instrumental investigations (test and treat). In most cases a well-taken history is usually sufficient to confirm the diagnosis of GERD and initiate treatment. However, some patients may present with ''atypical'' symptoms, classic symptoms refractory to standard medical therapy or ''alarm'' symptoms. In these cases, one must rely on diagnostic studies to document the presence of mucosal damage related or not to GERD and/or quantify the degree of gastro-esophageal reflux. The most relevant test to diagnose esophageal injury and complications of GERD is represented by upper gastrointestinal endoscopy, while the most diffuse procedure to quantify the degree of acid reflux is pH monitoring. Further studies are required to delineate the appropriate use and the possible impact of new techniques, such as intraluminal impedance monitoring, Bilitec and, wireless ambulatory pH monitoring in the management of GERD.