Endoscopic retrograde cholangiopancreatography (ERCP) is becoming more common than first-line therapy for pancreaticobiliary duct disorders. However, post-ERCP pancreatitis is the most common complication of ERCPs, and affects about 10% of cases. In this review, we provide an overview of the mechanisms purported to cause post-ERCP pancreatitis as well as associated risk factors. We discuss measures that are in practice for post-ERCP pancreatitis pharmaco-prophylaxis, along with advances in the pipeline. We emphasize that there is still a pressing need to narrow the incidence of post-ERCP pancreatitis and that a mechanistic approach may reveal the greatest benefit from utilizing a combination of targets.