Pancreatic ductal adenocarcinoma is the 10th most common cancer and the fourth leading cause of cancer-related death in the United States. Despite great effort, the prognosis for patients with this disease remains dismal with a 5-year survival rate of just 4% to 6%. Although several important advances have improved our understanding of the underlying biology of pancreatic cancer, this knowledge has not translated into novel therapeutic approaches and effective systemic or targeted therapies. Pancreatic cancer is one of the malignancies most difficult to treat, with remarkable intrinsic resistance to both standard and targeted chemotherapy as well as ionizing radiation. Surgical intervention remains the only potentially curative approach. However, most patients present with inoperable and/or metastatic disease and are therefore excluded from surgery. Accordingly, new therapeutic options are desperately needed. In vivo models to study innovative and alternative treatment approaches are of major importance. A variety of genetically engineered mouse models of pancreatic cancer have been developed over the last decade. However, these models display different characteristics, and not all of them are suited for preclinical studies. In this review, we aim to review the mouse models available, their experimental use, their clinical relevance and limitations, and future directions.