Pancreatic ductal adenocarcinoma (PDAC) represents the fourth leading cause of cancer-related deaths in the United States, with a 5-year survival rate of only 2% to 10%. This tumor is aggressive, often metastasizing to distant sites (liver, lung, and adjacent intestines) by the time of diagnosis. Treatment options are limited, and the disease carries a grave prognosis for most patients. An orthotopic model of human PDAC in nude mice provides an excellent way to evaluate the pathogenesis of tumor growth and metastasis in order to develop therapies, to better define the underlying biology of tumor growth and metastasis, and to identify new molecular targets. This unit describes an orthotopic model of human PDAC in athymic nude mice that closely mimics the human condition. It is characterized by diffuse peritoneal, lymphatic, and hepatic metastatic spread and manifestations of a cancer cachexic phenotype.