Third space endoscopy or intramural endoscopy is based on the principle that the deeper layers of the gastrointestinal tract can be accessed by tunneling in the submucosal space and maintaining the integrity of the overlying mucosa. The era of third space endoscopy started with peroral endoscopic myotomy (POEM) for treatment of achalasia and has expanded to treat various other gastrointestinal disorders. The technique is also currently used for treatment of refractory gastroparesis, Zenker’s diverticulum (ZD), resection of subepithelial tumors and early cancers of the gastrointestinal tract and Hirschsprung’s disease (HD). These procedures are rapidly emerging as minimally invasive alternatives to conventional surgery. They are safe and effective with excellent outcomes. This review focuses on the evolution and current applications of third space endoscopy in various gastrointestinal disorders. Key points: (1) Third space or intramural endoscopy initially started with the POEM procedure for treatment of achalasia; (2) Advancements in procedural techniques have expanded its application to treat other gastrointestinal disorders such as refractory gastroparesis, ZD, HD, resection of subepithelial tumors and early gastrointestinal cancers; (3) These procedures are highly effective with excellent outcomes and low complication rates; and (4) Third space endoscopic procedures are rapidly emerging as minimally invasive alternatives to conventional surgery.