Pancreatic cancer (PC) is the fourth leading cause of cancer death in the United States. Despite significant improvement in understanding disease biology, the 5-year survival rates remain less than 5%. Targeted agents failed to add any meaningful survival benefit in this patient population despite very promising pre-clinical data. The new paradigm for the treatment of PC must emphasize validation of targeted agents in the appropriate pre-clinical models, identification of predictive markers for disease response, and extending range of targets into cancer stem cells and tumor microenvironment. It is also necessary to perform studies that are designed to address the various stages of disease with respect to study endpoints and application of a multimodality approach in management. Phase III trials should only be considered when a strong efficacy signal is demonstrated in phase II studies that is based on a survival endpoint. This review will focus on the development of novel treatments in pancreas cancer and the proposed design of future clinical trials.