The goal of multimodality therapy for localized pancreatic cancer is to maximize local-regional disease control and patient survival. In contrast to surgery for other solid tumors, prolonged recovery following pancreaticoduodenectomy may prevent the timely delivery of postoperative adjuvant therapy. Therefore, efforts at The University of Texas, M.D. Anderson Cancer Center have focused on the delivery of chemotherapy and radiation therapy prior to surgery in patients with localized pancreatic cancer. Clinical trials have emphasized the use of altered-fractionation schedules of radiation therapy combined with novel radiation-sensitizing agents. All treatment schemes aim to decrease toxicity and treatment time while improving therapeutic efficacy.