We define mixed esophageal disease (MED) as a disorder of esophageal structure and/or function that produces variable signs or symptoms, simulating-fully or in part other well-defined esophageal conditions, such as gastroesophageal reflux disease, esophageal motility disorders, or even neoplasia. The central premise of the MED concept is that of an overlap syndrome that incorporates selected clinical, endoscopic, imaging, and functional features that alter the patient's quality of life and affect natural history, prognosis, and management. In this article, we highlight MED scenarios frequently encountered in medico-surgical practices worldwide, posing new diagnostic and therapeutic challenges. These, in turn, emphasize the need for better understanding and management, aiming towards improved outcomes and prognosis. Since MED has variable and sometimes time-evolving clinical phenotypes, it deserves proper recognition, definition, and collaborative, multidisciplinary approach, be it pharmacologic, endoscopic, or surgical, to optimize therapeutic outcomes, while minimizing iatrogenic complications. In this regard, it is best to define MED early in the process, preferably by teams of clinicians with expertise in managing esophageal diseases. MED is complex enough that is increasingly becoming the subject of virtual, multi-disciplinary, multi-institutional meetings.