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Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive solid malignancies and is characterized by poor response to current therapy and a dismal survival rate. Recent evidence indicates that PDAC is associated with frequent, altered cellular signaling pathways. We review these key pathways as well as recent investigations in the area of pancreatic cancer stem cells. Unfortunately, most phase III randomized trials of targeted therapies have not shown a survival advantage in PDAC. However, there has been extensive laboratory and clinical research in these areas which has revealed mechanisms of resistance involved in targeting PDAC and has provided insights into the ineffectiveness of current therapies. Current investigations will hopefully provide better insights into improved therapies and understanding of ways to overcome chemoresistance in PDAC. In this article, we discuss the current research exploring altered signaling pathways in PDAC and potential therapeutic targets.