Endoscopic retrograde cholangiopancreatography (ERCP) is a technically-demanding procedure. The ability to selectively cannulate the bile duct and pancreatic duct (PD) quickly and atraumatically is the key to successful therapeutic ERCP, and to minimizing post-ERCP complications, especially pancreatitis (PEP). Prophylactic stenting of the PD has significantly reduced the risk of severe PEP. Difficult ERCP access refers to the length of time and number of attempts it takes to achieve deep cannulation of the desired duct. If biliary access cannot be achieved quickly, PD stenting over a guide wire is recommended, which facilitates further attempts to enter the bile duct. Familiarity with guide wires and needle knife papillotomy technique are necessary to achieve close to 100 % biliary cannulation. Anatomic abnormalities, from gastric outlet strictures, periampullary diverticula, and ampullary masses to surgical rearrangement of the upper GI tract, contribute to the difficulty of performing ERCP. Adjunctive techniques to overcome these problems include percutaneous transhepatic biliary access and endoscopic ultrasound (EUS)-guided puncture of the bile duct through the stomach or duodenal wall. Therapeutic EUS is emerging as a major tool in the management of pancreatic and biliary disease, and will likely replace many therapeutic ERCP techniques in the next decade.