Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy that is best treated in a multidisciplinary fashion using surgery, chemotherapy, and radiation. Adjuvant chemotherapy has shown to have a significant survival benefit in patients with resected PDAC. However, up to 50% of patients fail to receive adjuvant chemotherapy due to postoperative complications, poor patient performance status or early disease progression. In order to ensure the delivery of chemotherapy, an alternative strategy is to administer systemic treatment prior to surgery. Precision oncology refers to the application of diverse strategies to target therapies specific to characteristics of a patient’s cancer. While traditionally emphasized in selecting targeted therapies based on molecular, genetic, and radiographic biomarkers for patients with metastatic disease, the neoadjuvant setting is a prime opportunity to utilize personalized approaches. In this article, we describe the current evidence for the use of neoadjuvant therapy (NT) and highlight unique opportunities for personalized care in patients with PDAC undergoing NT.