Due to the limited efficacy of surgery in pancreatico-biliary cancer, perioperative treatment modalities are of high clinical interest. Adjuvant chemoradiation with protracted infusion 5-FU for these tumors is an attractive direction for continued clinical research and may increase local control. Improved local control may influence survival as has been demonstrated by the results of adjuvant chemoradiation for operable rectal cancer. Newer combinations of chemotherapy and external beam radiotherapy (ExBRT) will need to be tested. The results of combined modality therapy indicate that increased normal tissue reactions occur and caution must be exercised during treatment especially in the areas of nutrition and fluid balance. New treatment strategies with electron beam IORT are also investigating higher doses of radiotherapy than those achieved with ExBRT alone in order to achieve better permanent tumor eradication. Data from our institution have demonstrated the safety of aggressive preoperative chemoradiation, surgical resection and IORT. Prophylactic hepatic and whole abdominal chemoradiation for occult liver disease needs further testing in clinical trials, since the liver is the single most frequent site of failure outside the primary site.