Postoperative pancreatic fistula (POPF) is traditionally considered the Achilles’ heel of pancreatic surgery. The burden of pancreatic surgery is still largely dependent on pancreatic fistula occurrence and its sequelae, despite the technical refinements and the availability of effective surgical devices and adjuncts attained in the last decade. The present chapter synthesizes contemporary notions in the prediction, mitigation, and treatment of this complication, in order to provide the surgeon with an evidence-based, conceptual framework for decision-making. Differences between head- and body/tail resections will be accentuated given the distinct mechanisms fistula development. Unique, intraoperative techniques and adjuncts available to the surgeon will be discussed, as well as postoperative patient management algorithms. Finally, key points of a modern, step-up approach for treatment of clinically relevant fistula will be illustrated.