Pancreatic cancer is a lethal disease characterized by local invasion and early dissemination. It is resistant to conventional surgical, radiotherapeutic, and chemotherapeutic modalities. These interventions have had minimal impact on overall survival with very few patients enjoying long term survival. Over the past few years, 2'difluoro-2'deoxycytidine (gemcitabine) has demonstrated modest activity in this disease and investigations are proceeding to expand its role in combination with radiotherapy and other chemotherapeutic agents. In addition, the identification of the molecular defects underlying this disease has suggested molecular targets for the design of rational systemic therapy. These targets include matrix metalloproteinases, K-ras, HER2/neu, p53, and the epidermal growth factor receptor. Current and future clinical trials designed to improve the survival of patients with pancreatic cancer will be discussed.