Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the Western world. The disease has the worst prognosis in the gastrointestinal malignancies with an overall 5-year survival rate of less than 5 %. Therefore, in the search for novel therapeutic targets, biomarkers for early detection and particularly adequate methods to develop and validate therapeutic strategies for this disease are still in urgent demand. Although significant progress has been achieved in understanding the genetic and molecular mechanisms, most approaches have not yet translated sufficiently for better outcome of the patients. In part, this situation is due to inappropriate or insufficient methods in modeling PDAC in laboratory settings. In the past several years, there has been an explosion of genetically engineered mouse models (GEMM) and patient-derived xenografts (PDX) that recapitulate both genetic and morphological alterations that lead to the development of PDAC. Both models are increasingly used for characterization and validation of diagnostic and therapeutic strategies. In this chapter we will discuss state-of-the-art models to consider when selecting an appropriate in vivo system to study disease etiology, cell signaling, and drug development.