The concept of using natural orifices to reduce the complications of surgery, Natural Orifices Transluminal Endoscopic Surgery, has also been applied to therapeutic endoscopy. Endoscopic submucosal surgery (ESS) provides more treatment options for various gastrointestinal diseases than traditional therapeutic endoscopy by using the submucosal layer as a working space. ESS has been performed in various fields ranging from transluminal peritoneoscopy to peroral endoscopic myotomy. With further advances in technology, ESS will be increasingly useful for diagnosis and treatment of gastrointestinal diseases.