Acute pancreatitis is the most common complication of endoscopic retrograde cholangiopancreatography (ERCP), occurring in up to 30 to 40% of high risk patients. The most prominent theories of post-ERCP pancreatitis (PEP) pathogenesis include mechanical trauma to the papillary orifice, hydrostatic injury, and enzymatic injury from activated proteolytic enzymes introduced from the duodenum. Investigators have proposed a number of patient-related, procedure-related, and physician-related risk factors for PEP. However, when evaluated in large prospective trials, the role of these factors in increasing risk of PEP is inconsistent. Placement of a pancreatic duct stent and administration of rectal non-steroidal anti-inflammatory drugs (NSAIDs) are the two interventions with the greatest body of evidence supporting efficacy in PEP prevention.