The most common and potentially devastating complication of endoscopic retrograde cholangiopancreatography (ERCP) remains post-ERCP pancreatitis (PEP). Recent advances in prophylaxis have reduced but not eliminated the risk of PEP. This review aims at providing an evidence-based, clinically applicable approach to PEP-prevention through patient selection, risk assessment, optimisation of procedural techniques, and multimodality prophylaxis.