Surgical resection alone for patients with adenocarcinoma of the pancreas has rarely resulted in cure, and long-term survival is uncommon. The magnitude of the operation has historically prevented many patients from receiving multimodality therapy with systemic chemotherapy or radiation (external beam and intraoperative). Improved rates of operative morbidity and mortality, technical advances in intraoperative radiotherapy, and encouraging results from studies combining radiation and chemotherapy have renewed interest in innovative treatments for this disease. We review the rationale for the current management of patients with resectable and locally advanced adenocarcinoma of the pancreas and the current trial at The University of Texas M.D. Anderson Cancer Center.