The tumor associated stroma has been described in recent years as being complicit in tumor growth in pancreatic cancer. The stroma hosts a variety of components of both cellular and molecular makeup. In normal tissues, the stroma provides nutrients and regulatory signals for proper cellular polarity and function. However, following oncogenic transformation, the stromal compartment is conscripted to provide stimulatory signals and protection to tumor cells. It is these tumor-stromal interactions that are currently of great therapeutic interest. Several key reports have suggested that therapeutic targeting of the tumor-stromal interactions in pancreatic cancer has the potential to offer survival benefit. In this review, we will discuss the tumor-stromal interactions that contribute to tumor growth and progression, and ways in which we might counter these interactions.