Systemic chemotherapy for advanced pancreatic cancer is commonly used in practice; however, the optimal strategy for both neoadjuvant and adjuvant therapy in this disease remains controversial. A particular challenge remains in patients who are considered to be locally advanced and either unresectable or borderline resectable. Offering optimal neoadjuvant therapy to this group of patients may give them the opportunity to have a curative surgical approach. This article will discuss the potential role of neoadjuvant therapy in borderline, potentially resectable pancreatic cancer. It will also discuss areas of interest in potential targets as the biology of pancreatic adenocarcinoma is further explored.