The purpose of this article is to provide a critical review of the current systemic treatment and the emerging targeted therapeutic strategies in pancreatic adenocarcinoma. Cytotoxic chemotherapeutic drugs have been used for palliative treatment of pancreatic adenocarcinoma, as well as for neoadjuvant therapy to facilitate surgical resection, and as adjuvant therapy to prevent tumor recurrence. The recent findings of early metastasis of cancer cells in pancreatic adenocarcinoma provide support for systemic therapy even in the case of small and localized tumors. However, the clinical benefits of systemic chemotherapy are generally limited and it is typically associated with a multitude of toxicities. Cancer-specific therapies with improved efficacy and safety are urgently needed. Tremendous advances have been made in understanding the biology and genetic regulation of normal and neoplastic development of the pancreas. These have led to identification of molecular targets in pancreatic cancer cells, the tumor microenvironment, and the cancer stem cells. Tumor-specific modalities are emergent by exploitation of the aberrant signaling pathways and molecular alterations in pancreatic cancer with the goals of improving treatment response. Integrative approaches that combine various targeting strategies with molecular bioinformatics will hopefully lead to the development of personalized therapies that may produce a positive impact on the quality of life and survival for patients with this deadly disease.