To date, pancreatic cancer has proved to be one of the most resistant malignancies, characterized by early local invasion and distant spread. Therefore, resection with curative intent is limited to a very small proportion of patients. Even in this select group, long-term survival remains very poor. Although radiotherapy and chemotherapy may provide some palliative benefits, these interventions have had minimal impact on overall survival. Over the past several years, 2'-difluoro-2'-deoxycytidine (gemcitabine) has demonstrated modest activity in advanced disease, and investigations are proceeding to expand its role in the adjuvant setting, in combination with radiotherapy, and in combination with other agents. In addition, several new cytotoxic agents are being tested for efficacy in pancreatic cancer. Although these drugs may demonstrate clinically meaningful anti-tumor activity, none of them is expected to dramatically alter the natural history of this disease. However, with the identification of the molecular events involved in pancreatic carcinogenesis, invasion, and metastasis, new agents with specific molecular targets are being developed and tested in the clinic. These targets include matrix metalloproteinases, the K-ras oncoprotein, the tumor suppressor p53, HER2, epidermal growth factor receptor, and vascularendothelial growth factor. These molecular approaches provide an exciting opportunity to improve outcomes for patients with pancreatic cancer.