Despite advances in diagnosis and therapy, pancreatic cancer remains a formidable challenge, and the prognosis is very poor. According to the American Cancer Society, an estimated 43,140 new cases of pancreatic cancer will be diagnosed in the United States during 2010, and 36,800 will die of this disease. There is no method for the early detection of this cancer; the early stages are asymptomatic. For most patients, pancreatic cancer is not detected until the disease is advanced. Only 7% of cases are diagnosed at an early stage. Surgery can be curative; however, only 5% to 20% of patients are candidates for surgery. Even then, the 5-year relative survival rate is only 10% to 22%, and approximately 50% of patients experience local recurrence. Pancreatic cancer is difficult to treat as demonstrated by the survival statistics. For all stages combined, the 1- and 5- year relative survival rates are 25% and 6%, respectively. To improve outcomes for patients with pancreatic cancer, multimodal treatment approaches including intraoperative radiation therapy (IORT) have been investigated.