Mouse models are important in the study of pathogenesis, testing new treatment, and monitoring the progress of treatment in patients with esophageal squamous cell carcinoma (ESCC). The mice commonly used are immunosuppressed. The first category of models is for basic research and includes genetically engineered mouse models and carcinogen- or diet-induced mouse models. The second category of models involves either injection of cells with altered gene function related to pathogenesis of ESCC or ESCC cell lines. This method is commonly used and relatively inexpensive and simple to use. These cells commonly being subcutaneous injected in flank (subcutaneous xenograft model), tail vein, or peritoneum of immunodeficient mice. Direct implantation into the esophagus (orthotopic xenograft model) is also performed despite the cost and technical difficulties. The third category of mouse model is the patient-derived xenograft (PDX) model. In this model, ESCC tissues (instead of cell lines) removed from the patient are implanted into immunodeficient mice. This model appears promising for personalized medicine and of high resemblance to the nature of human ESCC, but there are many limitations for the use. It is likely to be used more in research in ESCC in the future. In this chapter, we detailed the preparation and experiments of PDX model from a patient with ESCC.