Adjuvant 5-fluorouracil and concurrent radiation may improve survival following complete surgical resection in patients with pancreatic adenocarcinoma. However, the morbidity and prolonged recovery associated with pancreaticoduodenectomy frequently prevents the timely delivery of postoperative chemoradiation. Therefore, the University of Texas M.D. Anderson Cancer Center (MDACC) has investigated the use of neoadjuvant chemoradiation in potentially resectable pancreatic cancer. We have incorporated a standardized approach to pretreatment staging, operative technique and pathologic evaluation. Our initial experience suggests that preoperative chemoradiation is well tolerated and may reduce loco-regional recurrence. Patients treated with rapid-fractionation preoperative chemoradiation had a significantly shorter duration of treatment compared with patients who received postoperative chemoradiation or standard-fractionation preoperative chemoradiation. New and more potent radiation-sensitizing agents such as gemcitabine may further enhance local control. Novel therapies directed at specific molecular events involved in pancreatic tumorigenesis may be incorporated into preoperative and postoperative regimens to attempt to reduce systemic relapse.