Recent advances in minimally invasive endoscopic approaches have pushed the boundaries of well-established resection techniques for therapeutic and diagnostic applications. Endoscopic full thickness resection techniques are a key development in the management of challenging epithelial and subepithelial lesions that are not amenable to conventional endoscopic resection methods and previously required a surgical approach. Endoscopic full thickness biopsy represents a paradigm shift in tissue acquisition and will enhance our understanding of the pathophysiology, and guide therapy of gastrointestinal neuromuscular diseases, as well as other inflammatory and neoplastic conditions.