Novel approaches to the management of pancreatic cancer. Pancreatic cancer, including pancreatic adenocarcinoma, pancreatic ductal adenocarcinoma, and other types of malignancies such as neuroendocrine carcinoma, lymphoma and squamous cell carcinoma of the pancreas, represents a disease in which the lack of success in therapy may in part be explained by the complex biology of the disease. Many of the current treatment strategies for cancer in general have had little success in pancreatic cancer. Chemotherapy using the standard regimen of gemcitabine with or without erlotinib has yielded only marginal clinical benefit and may be associated with toxicity. Surgery is still the best option for a selected group of patients. The only option in non-resectable patients is gemcitabine, but the response rate is low. Therefore, for patients with locally advanced or metastatic pancreatic cancer, systemic therapies are used to slow disease progression and extend survival. Clinical studies have investigated the efficacy of gemcitabine and erlotinib in combination with or without oxaliplatin and with or without radiation therapy in the treatment of pancreatic cancer. Phase II and III studies have been performed to evaluate the efficacy of the newer, targeted agents capecitabine and oxaliplatin, and combination treatment with capecitabine and oxaliplatin, as well as docetaxel, irinotecan, epirubicin and cisplatin with fluorouracil. This article reviews the clinical development of these targeted agents in the treatment of pancreatic cancer. The potential use of molecular targeted agents will offer hope for a substantial number of patients with advanced pancreatic cancer in the near future.