The increased invasiveness of endoscopic procedures and complex surgical interventions has resulted in an increased number of gastrointestinal iatrogenic defects, such as perforations, leak and fistulas. The conventional treatment for these gastrointestinal defects is surgery, with considerable risks especially in emergency situations and in patients with comorbidities. The Ovesco over-the-scope clip (OTSC) system (Ovesco Endoscopy AG, Tübingen, Germany) and more recently, the Padlock Clip™ (Aponos Medical, Kingston, NH, USA) have shown promising results in the treatment of gastrointestinal defects. Several case reports and case series have demonstrated the efficacy of the OTSC system for the closure of full-thickness defects. Clinical success is best achieved in patients undergoing closure of a perforation or a leak. Closure of fistulas remains a clinical challenge since fibrosis or necrotic and inflamed tissue surrounding lesions may cause clip failure. Over-the-scope clips are a less invasive endoscopic option for managing patients with gastrointestinal defects before a more invasive surgical approach is attempted. Moreover, a failed attempt of OTSC deployment does not preclude subsequent surgical treatment.