Pancreatic ductal adenocarcinoma (PDAC) is the most common pancreatic neoplasm, representing 90% of all pancreatic cancers. In 2023, there will be an estimated 64,050 cases, and by 2040, PDAC is projected to be the second leading cause of cancer-related death (Siegel et al., CA Cancer J Clin 73:17–48, 2023). Given this malignancy’s propensity for distant progression, treatment almost always involves systemic therapy, and for eligible patients, the addition of pancreatic resection offers the only chance of cure. Historically, PDAC prognosis has been grim, but advances in systemic therapy and perioperative care have helped tip 5-year overall survival to 12%. Basic science and translational research focused on the tumor microenvironment, immunomodulation, and genomics, as well as innovative clinical trials exploring the optimal sequence of multimodal therapy, offer optimism for the future of PDAC management. This chapter highlights the clinical presentation, diagnosis, and current treatment of this challenging neoplasm.