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Pancreatic cancer is one of the most aggressive malignancies worldwide, with a very low survival rate after diagnosis. KRAS mutation is an early event in pancreatic tumorigenesis and is critical for cancer initiation and progression. Elucidating the underlying mechanisms regulating pancreatic organogenesis may help to identify molecular pathways underlying exocrine pancreatic carcinogenesis. The great progress in mouse models of pancreatic cancer has raised expectations, however, the results of preclinical trials of most new drugs that have shown good efficacy against invasive pancreatic ductal adenocarcinoma in mouse models have not been confirmed in the clinical stage. Addressing this fundamental problem may require the development of new animal models.