Pancreatic adenocarcinoma has one of the worse prognoses of any cancer with a 5-year survival of only 3%. Pancreatic cancer displays one of the most prominent stromal reactions of all tumors and it is evident that this is a key contributing factor to disease outcome. The tumor microenvironment of pancreatic cancer harbors a wide spectrum of cell types and a complex network of mechanisms which all serve to promote tumor progression. It is clear that the symbiotic relationship between pancreatic cancer cells and stellate cells is the chief factor creating this unique tumor milieu. Pancreatic stellate cells play critical roles in evasion of cancer cell apoptosis, invasion and metastases, angiogenesis, and promotion of an immunosuppressive environment, all key hallmarks of malignancy. Existing treatments for pancreatic cancer focus on targeting the cancer cells rather than the whole tumor, of which cancer cells represent a small proportion. It is now increasingly evident that research targeted towards the interactions between these cell types, ideally at an early stage of tumor development, is imperative in order to propel the way forward to more effective treatments. Copyright © 2012 IAP and EPC. Published by Elsevier B.V. All rights reserved.