This article will review the pertinent data on the use of chemotherapy for all stages of pancreatic cancer. For patients with metastatic disease, fluorouracil (5-FU) was the standard of care for several decades until a single randomized trial established that gemcitabine (Gemzar) produced a greater clinical benefit response, median survival, and 1-year survival. Among the currently available chemotherapy agents, the taxanes, fluoropyrimidines, and camptothecins are being evaluated in clinical trials alone or in combination with gemcitabine. Newer agents that are not classically cytotoxic are also under investigation and hold promise for the future. In patients with locally advanced unresectable disease, chemotherapy is commonly used to sensitize the cancer to radiation. Current investigations focus on trying to improve chemotherapy as a radiation sensitizer, using, for example, infusional 5-FU and gemcitabine. Early-stage, surgically resectable patients may benefit from the combination of chemotherapy and radiation, although more recent trials conducted in Europe raise some doubt. However, flaws in trial design do not allow firm conclusions to be drawn about the benefits of adjuvant therapy. Both chemotherapy and chemoradiation are under further investigation. Significant improvements in the survival of patients with pancreatic cancer will be achieved as more effective systemic therapies are developed, including agents with novel cellular targets.