Pancreatic cancer is a devastating illness that has the briefest survival of any solid tumor. Gemcitabine, the standard chemotherapy, improves quality of life and modestly improves response rates and survival compared with 5-fluorouracil. Several single agents have been compared with gemcitabine in phase III trials; none have proven superior to gemcitabine. Similarly, no statistically significant improvement in survival has been observed in multiple phase III trials when doublets of gemcitabine plus a cytotoxic drug have been compared with single-agent gemcitabine. Fixed-dose rate administration has also been evaluated to improve the efficacy of gemcitabine. It appears unlikely that cytotoxic chemotherapy will substantially alter the natural history of this chemo-refractory disease. New agents targeted against specific molecular events involved in pancreatic carcinogenesis, invasion, and metastasis may be more worthy of evaluation than additional gemcitabine doublets. Agents that target vascular endothelial growth factor and the epidermal growth factor receptor are currently being evaluated in phase III trials.