Endoscopic retrograde cholangiopancreatography (ERCP) is one of the most technically challenging therapeutic endoscopic procedures. The primary condition for successful implementation of ERCP is biliary cannulation, which has a success rate of about 75%-85% with conventional standard biliary cannulation technique, but there is still 8.1% of patients with difficult biliary cannulation. At present, there is no unified international consensus on the definition of difficult cannulation, and most studies define difficult biliary cannulation based on the number of cannulation attempts and/or duration of cannulation. The occurrence of difficult cannulation depends on some uncontrollable factors such as patient anatomy (eg, diverticulum papilla, thick and long duodenal papilla, abnormal confluence of biliopancreatic duct, etc.), disease-specific factors (eg, duodenal papilla or ampulla tumor, biliary lithoyomy after digestive tract reconstruction, etc.), and operators' experience. Difficult cannulation is closely associated with the increase of adverse events after ERCP, of which post-ERCP pancreatitis (PEP) is the most common and serious complication. Therefore, early risk stratification of population with high-risk of PEP is crucial. At present, an increasing number of scholars are attempting to develop clinically practical PEP risk prediction score systems. When difficult intubation is encountered, the overall success rate of bile duct intubation can be increased to 95% by using advanced rescue intubation techniques. The current commonly used rescue intubation techniques based on ERCP mainly include double-guidewire technique, wire-guided cannulation over a pancreatic stent, transpancreatic precut sphincterotomy, needle-knife precut papillotomy, and needle-knife precut fistulotomy. However, these advanced techniques also increase the risk of complications and their implementations are limited by factors such as the anatomical structure of the duodenal papilla, the process of the guidewire insertion into the pancreatic duct, and the skill level of the surgeon. If cannulation still fails despite the use of above-mentioned rescue intubation techniques, the operation should be terminated immediately and a second ERCP should be considered to be performed a few days later, in combination with the measures such as percutaneous transhepatic cholangial drainage, percutaneous transhepatic gallbladder drainage, and the newer endoscopic ultrasound (EUS)-guided interventions, EUS-guided rendezvous or EUS-guided anterograde interventions. The purpose of this paper is to describe the definition, related risk factors and adverse impacts of difficult cannulation, to review and compare the safety and effectiveness of different rescue intubation techniques, and to discuss the selection and application of different rescue intubation techniques from different difficult intubation scenarios. In addition, this article also introduces the alternative measures and the selection basis after the failed cannulation in the first ERCP procedure, so as to provide a reference for the establishment of standardized ERCP intubation procedure in clinical practice.