Recently, increasingly invasive therapeutic endoscopic procedures and more complex gastrointestinal surgeries such as endoscopic mucosal resection, endoscopic submucosal dissection, and novel laparoscopic approaches have resulted in endoscopists being confronted more frequently with perforations, fistulas, and anastomotic leakages, for which nonsurgical closure is desired. In this article, we present our experiences with the use of over-the-scope clip (OTSC) for natural orifice transluminal endoscopic surgery (NOTES) closure, prevention of perforation, anastomotic leakages, and fistula closures. The OTSC is a valuable device for closing intestinal perforations and fistulas, for NOTES closure, and for the prevention of perforation after the excision of a tumor from the proper muscle layer. Furthermore, it seems to be quite safe to perform, even by endoscopists with little experience of the technique.