Pancreatic cancer is a devastating disease with historically limited success in treatment and a poor prognosis. Pancreatic cancer appears to have a progressive pathway of development, initiating from well‐described pancreatic intraepithelial neoplasia lesions and concluding with invasive carcinoma. These early lesions have been shown to harbor‐specific alterations in signaling pathways that remain throughout this tumorigenesis process. Meanwhile, new alterations occur during this process of disease progression to have a cumulative effect. This series of events not only impacts the epithelial cells comprising the tumor, but they may also affect the surrounding stromal cells. The result is the formation of complex signaling networks of communication between the tumor epithelial cell and the stromal cell compartments to promote a permissive and cooperative environment. This article highlights some of the most common pathway aberrations involved with this disease, and how these may subsequently affect one or both cellular compartments. Consequently, furthering our understanding of these pathways in terms of their function on the tumoral epithelial and stromal compartments may prove to be crucial to the development of targeted and more successful therapies in the future. © 2011 Wiley Periodicals, Inc.