One of the defining features of pancreatic ductal adenocarcinoma (PDAC) is the presence of extensive desmoplasia. The desmoplastic stroma consists of proliferating fibroblasts and pancreatic stellate cells that produce and deposit fibronectin and collagens, inflammatory cells and macrophages that produce chemokines and cytokines, nerve fibers that release nerve growth factors, and marrow-derived stem cells. Stroma production is facilitated by the abundance of growth factors, including fibroblast growth factors (FGFs), epidermal growth factor (EGF) receptor ligands, transforming growth factor-beta (TGF-beta) isoforms, and connective tissue growth factor. Due to its location in the pancreas, stromal cells and pancreatic cancer cells are also exposed to high insulin levels. The stromal compartment stores and synthesizes multiple growth factors and the heparan sulfate proteoglycans glypican-1 and syndecan-1. This unique microenvironment harbors and nourishes the cancer cells, facilitating their invasive and metastatic potential. Targeting the stroma may thus provide novel therapeutic options in this deadly malignancy.