Adenocarcinoma of the pancreas is a very disappointing disease. By the time of diagnosis, most patients have extensive metastasis, primarily to the liver, peritoneum, and the lymph system. At this point, the disease is usually too advanced to allow resection. Even if resection is performed, the recurrence rate is high. Therefore, there is an urgent need to develop non-surgical therapies. This paper reviews the current role of chemotherapy in pancreatic adenocarcinoma. Various single agent and multiple agent therapies for advanced and locally advanced pancreatic adenocarcinoma are reviewed and discussed. The role of chemotherapy as an adjuvant therapy to surgical resection is also covered in this paper.