The genetic paradigm of cancer, focused largely on sequential molecular aberrations and associated biological impact in the neoplastic cell compartment of malignant tumors, has dominated our view of cancer pathogenesis. For the most part, this conceptualization has overlooked the dynamic and complex contributions of the surrounding microenvironment comprised of non-tumor cells (stroma) that may resist, react to, and/or foster tumor development. Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease in which a prominent tumor stroma compartment is a defining characteristic. Indeed, the bulk of PDAC tumor volume consists of non-neoplastic fibroblastic, vascular, and inflammatory cells surrounded by immense quantities of extracellular matrix, far exceeding that found in most other tumor types. Remarkably, little is known about the composition and physiology of the PDAC tumor microenvironment, in particular, the role of stroma in tumor initiation and progression. This review attempts to define key challenges, opportunities and state-of-knowledge relating to the PDAC microenvironment research with an emphasis on how inflammatory processes and key cancer pathways may shape the ontogeny of the tumor stroma. Such knowledge may be used to understand the evolution and biology of this lethal cancer and may convert these insights into new points of therapeutic intervention. J. Cell. Biochem. 101: 887–907, 2007. © 2007 Wiley-Liss, Inc.