Introduction: This review provides an overview of the molecular mechanisms and pathways known to enhance development and progression of pancreatic ductal adenocarcinoma (PDAC). Results: Today, the concept that progression of epithelial precursor lesions leads to invasive PDAC as a result of accumulating mutation in K-ras, p16INK4A, p53 and Smad4 is widely accepted. Multiple signaling pathways that PDAC utilizes to acquire its tumorigenic features have been identified. Recent data suggest that reactivated developmental signaling pathways play a role in oncogenesis of PDAC. Furthermore, it is now clear that the tumor microenvironment actively promotes invasion and tumor growth through a complex of interactions of different cellular components. Conclusion: PDAC is still a challenging entity for physicians and scientists. Despite of recent advances in understanding its molecular biology, treatment options remain limited. Distinct tumor stroma interactions and apoptotic resistance lead to frequent failure of current chemotherapy. An early and aggressive tumor infiltration in combination with a late diagnosis prevents successful surgical therapy. Thus, our primary goal remains to translate the increasing knowledge of molecular pathogenesis of this disease into successful therapeutic strategies. Apart from tumor cell biology, the complex interactions of PDAC cells with their microenvironment have to be focus of future molecular research.