There are now more than 25 years of experience with the endoscopic use of cyanoacrylate glues in the GI tract. In patients with bleeding or large fundal gastric varices, glue treatment is widely considered the standard of care, with high hemostasis rates during acute bleeding and efficacy in bleeding prevention and variceal obliteration as secondary and primary prophylaxis. Embolization is a rare, but potentially lethal, complication. The combination of EUS-guided coil placement before glue injection may reduce the embolization risk. Ocrylate appears to be at least equivalent to enbucrilate in terms of safety and is easier to administer under EUS guidance because of a longer polymerization time. In acute esophageal variceal bleeding, glue treatment may be useful for very large varices or varices refractory to conventional band ligation. EUS guidance deserves further study to avoid extravariceal injection into the esophageal wall. Cyanoacrylate injection appears well-suited as a means of sealing leaks refractory to standard endoscopic treatment by sphincterotomy and plastic stenting in the biliary tree and the main pancreatic duct. In a majority of cases, leak closure is accomplished after a single treatment. Because of its significantly lower cost, glue injection may be preferable to the use of CSEMSs as the next step for refractory biliary leaks, particularly for intrahepatic leaks. Significant numbers of case reports and some series suggest that cyanoacrylate glue may have a role in the sealing of GI fistulas in patients not suitable for surgery. Because of the lack of any controlled trials, true efficacy rates are not available, but data would suggest that glue is poory effective in healing inflammatory or malignant disease-related fistulas. Copyright © 2013 by the American Society for Gastrointestinal Endoscopy.