Pancreatic ductal adenocarcinoma (PDAC) presents significant challenges in diagnosis and treatment which have resulted in poor prognosis compared to other disease sites. The optimal sequencing of multimodal treatments for localized PDAC remains under active investigation at multiple centers across the globe. Following cross-sectional imaging and tissue diagnosis, treatment involves a combination of chemotherapy and surgery, with or without chemoradiation. Staging and classification of localized PDAC into resectable, borderline resectable, and locally advanced disease should occur in the setting of a multidisciplinary discussion, as should decisions on treatment sequencing. Delivery of multimodal therapies should be informed by tumor markers when feasible and should adapt to radiological and biomarker evidence of treatment response as well as to treatment toxicity. In this chapter, we discuss the oncologic advantages of neoadjuvant therapy in its historic context. We also discuss the importance of pancreatectomy at high-volume pancreatic surgery centers to optimize oncologic outcomes and minimize morbidity and mortality from surgery.