Pancreatic carcinoma is an unusually lethal disease and to date treatment with standard chemotherapy has yielded disappointing results. The epidermal growth factor receptor (EGFR) is known to be over-expressed in pancreatic cancer and there is data to suggest that this molecular characteristic may be a poor prognostic factor as it may denote a more aggressive form of the disease. Current therapeutic modalities to target the EGFR include monoclonal antibodies directed against the extracellular domain of the receptor as well as tyrosine kinase inhibitors that disable the activating portion of the receptor. Preclinical studies in pancreatic cancer models have demonstrated the efficacy of both of these treatment options and at present they are in various stages of clinical testing in combination with other cytotoxic drugs, with other biologic therapies and in conjunction with radiotherapy. The combination of gemcitabine and one of the tyrosine kinase inhibitors, erlotinib, is the first combination therapy to demonstrate survival benefits in pancreatic cancer in a phase III study albeit a modest one. Increased understanding of the EGFR pathway may permit the use of other targeted agents to either augment therapeutic efficacy or circumvent resistance. Additional EGFR targeted strategies for pancreatic cancer are being developed that may further circumvent mechanisms resistance to EGFR inhibition.