Despite improvements in endoscopic technologies and accessories, development of advanced endoscopy fellowship programs, and advances in ancillary imaging techniques, biliary cannulation in endoscopic retrograde cholangiopancreatography (ERCP) can still be unsuccessful in up to 20% of patients, even in referral centers. Once cannulation has been deemed to be difficult, the risk of post-ERCP pancreatitis and technical failure inherently increases. A number of factors, including endoscopist experience and patient anatomy, have been associated with difficult biliary cannulation, but predicting a case of difficult cannulation a priori is often not possible. Numerous techniques such as pancreatic guidewire and stenting, early pre-cut, and rendezvous may be employed when standard approaches fail. Data regarding the rate of success and adverse events of these techniques have been variable, though most studies suggest that pancreatic duct stenting generally reduces the rate of post-ERCP pancreatitis in instances of difficult biliary cannulation. Here we provide a review on difficult biliary cannulation and discuss how the choice of which techniques to employ and how to best employ them should be individualized and take into account the skill of the endoscopist, the disorder being treated, the anatomy of the patient, and the available biomedical literature.