Cell motility is controlled by the dynamic cytoskeleton and its related proteins, such as members of the ezrin/radixin/moesin (ERM) family, which act as signaling molecules inducing cytoskeleton remodeling. Although ERM proteins have been identified as important factors in various malignancies, functional redundancy between these proteins has hindered the dissection of their individual contribution. The aim of the present study was to analyze the functional role of moesin in pancreatic malignancies. Cancer cells of different malignant lesions of human and transgenic mice pancreata were evaluated by immunohistochemistry. For functional analysis, cell growth, adhesion, and invasion assays were carried out after transient and stable knock-down of moesin expression in pancreatic cancer cells. In vivo tumorigenicity was determined using orthotopic and metastatic mouse tumor models. We now show that moesin knock-down increases migration, invasion, and metastasis and influences extracellular matrix organization of pancreatic cancer. Moesin-regulated migratory activities of pancreatic cancer cells were in part promoted through cellular translocation of beta-catenin, and re-distribution and organization of the cytoskeleton. Analysis of human and different transgenic mouse pancreatic cancers, demonstrated that moesin is a phenotypic marker for anaplastic carcinoma, suggesting that this ERM protein plays a specific role in pancreatic carcinogenesis.