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Targeting the epidermal growth factor receptor (EGFR) with small molecule inhibitors or monoclonal antibodies in combination with chemotherapy and radiation is a theoretically appealing strategy in pancreatic cancer. EGFR inhibitors have shown efficacy as radiosensitizers and activity against metastatic pancreatic cancer when combined with gemcitabine. This paper examines the available clinical data, with a focus on locally advanced, unresectable disease. Further studies with a focus on understanding the basic biology of EGFR inhibition are needed to identify an optimal multi-modality regimen.