There is a continuing increase in gastroesophageal reflux disease (GERD), its diverse manifestations and complications worldwide. Indeed the substantial increase in Asia remains is a major epidemiologic and a developing health care issue. This manifesto provides a contemporary review of the current status of areas of uncertainty and in particular highlights the lack of knowledge and unmet needs in the field of GERD biology and especially management. There seems to be no widely accepted rationale for the increasing incidence and prevalence of GERD globally. Although consideration has been given to the decline in Helicobacter pylori infection, others consider the steadily growing problem of obesity as the most likely etiologic factor. What actually comprises the disease entity of GERD continues to confound physicians, and the steady increase in new definitions suggests that a clear picture is still emerging. Of note, however, is the rising awareness of its protean systemic manifestations and the fact that while erosive reflux disease is easily recognizable endoscopically, nonerosive disease (NERD) comprises the majority of presentations in many populations. In view of this, GERD-specific questionnaires and other evaluative tools have been designed to capture the multidimensional nature of the symptom complexes in GERD patients who for the most part may have no endoscopic evidence of disease. Such tools have obvious utility in the evaluation of changes with treatment, especially because there is no endoscopic abnormality detectable. The recognition that NERD is becoming a major clinical entity that requires substantial further investigation is now clearly apparent. At this time, however, little is known of the cellular barrier mechanisms of the esophagus and what is responsible for their reconstitution after injury. Similarly, the neural basis of esophageal pain appreciation, or its relation to the visceral sensory mechanisms that may link NERD with aspects of functional bowel disease are as yet ill understood. Apart from the clinical concern with symptom-focused issues, it is the specter of Barrett esophagus, the most-feared complication of GERD that mostly continues to drive endoscopic practice in GERD. At this time, however, current surveillance strategies remain severely limited in their ability to adequately detect or prevent most esophageal adenocarcinoma. Although considerable effort has been directed at defining the neural circuitry of the esophagus in terms of both motility and sensation, the topography and function of the esophageal-brain-gut axis in respect of the generation of esophageal symptoms remains terra incognita. At this time therefore acid suppression remains the mainstay of therapy in terms of treating the GERD/NERD disease process. Despite the efficacy of the currently available proton pump inhibitor class of drugs, there are clearly unmet needs in this area and agents with a more rapid onset of action and prolonged effect, particularly at night remain important goals in the future advance of pharmacotherapy.