Successful biliary cannulation is the prerequisite for subsequent endoscopic biliary therapy during endoscopic retrograde cholangiopancreatography (ERCP). Difficult cannulation is encountered in approximately 11% of therapeutic ERCPs and increases the risk of post-ERCP adverse events, particularly post-ERCP pancreatitis (PEP). Therefore, measures for prophylaxis of PEP should be implemented when difficult cannulation is encountered, including per rectal non-steroidal anti-inflammatory drugs (NSAIDs), pancreatic duct stent, and hydration. Various methods can be utilized to overcome difficult biliary cannulation, including pancreatic guidewire-assisted technique, pancreatic duct stent-assisted cannulation, precut, and transpancreatic biliary sphincterotomy. These techniques/procedures are more complex and may carry increased risk of complications. Repeat ERCP at another session, rendezvous technique, or EUS-guided biliary access can be considered when the above advanced techniques still fail to provide access to the bile duct.