Despite improvements in surgical management, only a minority of patients enjoy long-term survival following pancreaticoduodenectomy for adenocarcinoma of the pancreas. Adjuvant therapy consisting of 5-fluorouracil and irradiation has improved median and 5-year survival rates; however, at least one third of eligible patients do not receive postoperative adjuvant therapy because of delayed recovery following pancreaticoduodenectomy. This has led to the development of treatment schedules incorporating the delivery of systemic therapy and/or chemoradiation prior to surgery. This article briefly outlines the history of adjuvant therapy for adenocarcinoma of the pancreas and reviews the available literature on neoadjuvant therapy for localized pancreatic cancer including investigational therapies under clinical trial evaluation.