Borderline resectable pancreatic adenocarcinoma represents a subset of localized cancers that are at high risk for a margin-positive resection and early treatment failure when resected de novo. Although several different anatomic definitions for this disease stage exist, there is agreement that some degree of reconstructible mesenteric vessel involvement by the tumor is the critical anatomic feature that positions borderline resectable between anatomically resectable and unresectable (locally advanced) tumors in the spectrum of localized disease. Consensus also exists that such cancers should be treated with neoadjuvant chemotherapy and/or chemoradiation before resection; although the optimal algorithm is unknown, systemic chemotherapy followed by chemoradiation is a rational approach. Although gemcitabine-based systemic chemotherapy with either 5-FU or gemcitabine-based chemoradiation regimens has been used to date, newer regimens, including FOLFIRINOX, should be evaluated on protocol. Delivery of neoadjuvant therapy necessitates durable biliary decompression for as many as 6 months in many patients with cancers of the pancreatic head. Patients with no evidence of metastatic disease following neoadjuvant therapy should be brought to the operating room for pancreatectomy, at which time resection of the superior mesenteric/portal vein and/or hepatic artery should be performed when necessary to achieve a margin-negative resection. Following completion of multimodality therapy, patients with borderline resectable pancreatic cancer can expect a duration of survival as favorable as that of patients who initially present with resectable tumors. Coordination among a multidisciplinary team of physicians is necessary to maximize these complex patients' short- and long-term oncologic outcomes.