Post-ERCP pancreatitis (PEP) remains the most common complication following ERCP. Although once considered unpredictable, understanding patient and procedure-related risk factors, and measures such as pancreatic stent placement and pharmacoprophylaxis have been shown to substantially decrease the risk of PEP. In this issue of the Journal, the role of pharmacoprophylaxis is explored in a study comparing rectal indomethacin plus sublingual nitrates vs. rectal indomethacin alone. While showing improved efficacy, dual pharmacoprophylaxis does not appear adequate to obviate the importance of technique-related variables and pancreatic stents. Rather, a comprehensive approach is likely to be the most efficacious strategy to reduce PEP.