Recent technological advances in the field of gastroenterology have revolutionized the way endoscopy is used to manage both premalignant and malignant lesions throughout the gastrointestinal tract. For many decades, endoscopic treatment was limited to superficial mucosal lesions. However, with the advent of endoscopic mucosal resection in 1992, the armamentarium of the endoscopist started to expand. More recently, endoscopic submucosal dissection and endoscopic muscularis dissection have emerged as therapeutic methods for overcoming the limitations of endoscopic mucosal resection. For deep submucosal lesions that may be challenging or technically impossible to remove with these latter methods, is there a role for taking dissection even 1 step (ie, layer) further? To help answer this question, we address the preparation and identification of lesions that may be suitable for endoscopic full-thickness resection.