For over 25 years, the standard of care for resectable pancreatic adenocarcinoma has been upfront surgery followed by delivery of post-operative therapy. Until recently however, there has been no consensus as what constituted a standard adjuvant regimen. Data from large phase III studies now support single agent gemcitabine, administered over 6 cycles, as standard. Nevertheless, the overall survival of patients undergoing upfront surgical resection followed by adjuvant therapy remains poor, with no significant improvements in median, or long term survival over the last 3 decades. Surgery as the first intervention for potentially curative pancreatic cancer has some distinct disadvantages and neoadjuvant therapy provides a mechanism to better select patients for subsequent surgical intervention. Current data suggest this approach spares patients from a morbid surgical procedure when it will be of no benefit and improves outcomes for those who do undergo surgery. Furthermore, with the increasing recognition of borderline resectable pancreatic cancer, neoadjuvant treatment should be considered as alternative to upfront surgery for this distinct clinical entity. This has the potential to maximize the chances of a margin-negative resection and minimize the number of patients harboring aggressive disease from undergoing a fruitless surgical procedure. Importantly, as the number of targeted agents available for clinical use expands, more rational, personalized neoadjuvant therapies may emerge.