Cancer of the pancreas remains a formidable challenge in oncology. This malignancy ranks as the fourth leading cause of cancer death in the United States in 2003, with an estimated 30,700 new cases to be diagnosed and 30,000 deaths. Although gains have been achieved in the clinical management of these patients, this malignancy is rarely curable. Long-term survival is limited to patients undergoing resection. For patients with localized but unresectable malignancy, radiation therapy combined with fluorouracil, gemcitabine (Gemzar), or paclitaxel has shown modest improvements in survival and symptom palliation. However, there has been significant progress in the diagnostic evaluation of pancreatic cancer patients, which has aided clinicians in caring for these patients and in selecting therapies. The use of computed tomography, endoscopic ultrasonography, and laparoscopy techniques will be discussed. Newer techniques of radiation therapy, such as intraoperative electron-beam radiation therapy and three-dimensional conformal radiation therapy, with the integration of new biologically targeted agents may provide new avenues of research and progress in this disease.