Pancreatic cancer is accompanied with a fibrotic reaction that alters interactions between tumor cells and the stroma to promote tumor progression. Consequently, strategies to target the tumor stroma might be used to treat patients with pancreatic cancer. We review recently developed approaches for re-shaping the pancreatic tumor stroma and discuss how these might improve patient outcomes. We also describe relationships between the pancreatic tumor extracellular matrix, the vasculature, the immune system, and metabolism and discuss the implications for the development of stromal compartment-specific therapies.