In this episode of SurgOnc Today, Mark Knab, Charles Vining, and Kelvin Allenson discuss how the anatomic location of duodenal adenocarcinoma—from the first to the fourth portion—fundamentally shapes surgical decision-making. Discussion highlights include criteria for pancreaticoduodenectomy versus segmental or limited resections, the role of margin status and lymphadenectomy, and evolving data guiding resection strategy for non-ampullary duodenal cancers. Designed for practicing surgical oncologists, this episode emphasizes operative judgment, outcomes data, and the balance between oncologic adequacy and surgical morbidity.