Pancreatic cancer remains an important cause of cancer mortality with few long-term survivors. Improvement in the systemic therapy of pancreatic cancer is necessary to treat the frequently encountered metastatic disease. Several new chemotherapeutic agents with modest activity against pancreatic cancer have been identified over the past decade. Gemcitabine is currently the standard treatment for advanced pancreatic cancer. Combination chemotherapy trials incorporating gemcitabine, cisplatin, 5-fluorouracil, oxaliplatin, or irinotecan generally show improved outcomes in objective response rates but with little or no improvement in survival in phase III trials. Novel therapeutic strategies targeting dysregulated molecular pathways in pancreatic cancer cells are currently being explored. Future treatment regimens for pancreatic cancer will probably incorporate conventional cytotoxic drugs and novel targeted agents.