Only 5% to 15% of patients with pancreatic adenocarcinoma are candidates for a potentially curative resection. Evidence that postoperative adjuvant therapy improves outcome has been limited to a single randomized trial of a well tolerated split-course, 5-Fluorouracil (5-FU) based, chemoradiation regimen. More aggressive regimens have since been developed and are associated with, at best, a modest improvement in patient outcome. The potentially significant morbidity associated with pancreaticoduodenectomy, which can compromise the delivery of postoperative adjuvant chemoradiation, has led to the development of preoperative (adjuvant/neoadjuvant chemoradiation) regimens in these patients. Although experience suggests that such an approach is feasible, the ultimate impact warrants further evaluation. In addition, despite evolving experiences towards more dose intensive pre or postoperative adjuvant chemoradiation regimens, the problem of distant metastases remains significant. New chemotherapeutic agents, such as gemcitabine, appear to have the potential to produce better results than those achieved over the last quarter century with 5-FU. A cooperative group study has recently been activated and is evaluating its impact in an adjuvant setting when given in addition to 5-FU based chemoradiation. In the meantime, ongoing investigations into optimal integration of different therapeutic modalities, along with advances in surgery, radiation, and systemic therapy, should lead us towards further improvements in outcomes for these patients.