Although not universally accepted, chemoradiation is considered a standard adjuvant treatment for patients with resected pancreatic cancer. Theoretical advantages of reduced toxicity and increased efficacy with the use of pre-operative chemoradiation compared to post-operative adjuvant chemoradiation have recently been validated with the publication of a phase III trial in the adjuvant treatment of rectal cancer. Additional advantages of pre-operative chemoradiation that apply specifically to pancreatic cancer include increased access to therapy in patients treated before surgery, addressing the systemic disease recurrence risk without delay, and optimal patient selection for pancreaticoduodenectomy through exclusion of patients with rapidly progressive metastatic disease. Critical components of a pre-operative treatment strategy for pancreatic cancer include adherence to a strict definition of resectability, accurate radiographic staging capable of identifying patients with potentially resectable disease, and a safe and efficient means of obtaining a tissue diagnosis and relieving biliary obstruction. Herein, we discuss the rationale for the use of pre-operative chemoradiation in pancreatic cancer, the results of treatment, and future strategies to address the pattern of disease recurrence.