The over-the-scope clip (OTSC) system is increasingly used for the endoscopic hemostasis of bleeding non-variceal upper gastrointestinal lesions. OTSCs provide secure, full-thickness tissue compression. The Stop the Bleeding Trial (STING-1) was a German multicenter randomized controlled trial (RCT) that compared OTSC to standard treatment (through-the-scope clips and contact thermal devices) for refractory bleeding ulcers. The rate of further bleeding was significantly reduced with the use of OTSC (19 of 33 patients [57.6%] in the standard therapy group and 5 of 33 patients [15.2%] in the OTSC group). As a first-line endoscopic treatment, OTSCs have been compared with standard treatments in five RCTs, including the STING-2 trial. OTSCs are generally superior in controlling bleeding. Therefore, we recommend the use of OTSCs for lesions with a high risk of further bleeding. These include large ulcers (2 cm in size or larger) located at the duodenal bulb and the lesser curve of the stomach, and ulcers with vessels >2 mm in size. We have also used OTSCs for Dieulafoy’s lesions, often with thick submucosal arteries. An ongoing RCT is comparing the use of OTSCs with trans-arterial embolization (TAE) for refractory bleeding. TAE is considered the most definitive, but is associated with a 30% rate of further bleeding. The results of the RCT will help define the management algorithm for such cases.