Pancreatic adenocarcinoma is a highly lethal disease that is histologically characterized by a dense desmoplastic reaction (DR) surrounding malignant epithelial cells. The DR is composed of extracellular matrix (ECM) proteins, fibroblasts, stellate cells, endothelial cells, immune cells, and neurons. Accumulating evidence indicates that the epithelial and stromal compartments interact to enhance the aggressive nature of this disease. Pancreatic cancer cells release various factors that stimulate the stroma. Stromal cells, in turn, release mitogenic substances that stimulate tumor growth, invasion, and resistance to therapy. As we better understand the interactions between the stromal and epithelial cell compartments in pancreatic adenocarcinoma, it is becoming evident that anticancer therapies targeting the stroma, in addition to epithelial cells, may play a key role in improving clinical outcomes for patients with this deadly disease.