Despite advances in multidisciplinary oncology care, curing patients diagnosed with pancreatic duct adenocarcinoma (PDAC) remains all too uncommon. In this Review, we discuss evolving concepts to guide the care of patients with operable PDAC, focusing on adjuvant and neoadjuvant systemic therapies, the ever-controversial topic of radiation therapy, and the emerging role of cancer vaccines. Given the promise of biomarkers to better predict therapeutic response, the development of KRAS inhibitors, our ability to deliver higher doses of radiation therapy more precisely and safely, and the technology to rapidly produce highly personalized cancer vaccines, there is reason to expect that the guidelines for the care of our patients with operable PDAC will change rapidly in the next few years.