Esophageal cancer (EC) represents a human malignancy, diagnosed often at the advanced stage of cancer and resulting in high morbidity and mortality. The development of precision medicine allows for the identification of more personalized therapeutic strategies to improve cancer treatment. By implanting primary cancer tissues into immunodeficient mice for expansion, patient-derived xenograft (PDX) models largely maintain similar histological and genetic representations naturally found in patients’ tumor cells. PDX models of EC (EC-PDX) provide fine platforms to investigate the tumor microenvironment, tumor genomic heterogeneity, and tumor response to chemoradiotherapy, which are necessary for new drug discovery to combat EC in addition to optimization of current therapeutic strategies for EC. In this review, we summarize the methods used for establishing EC-PDX models and investigate the utilities of EC-PDX in screening predictive biomarkers and potential therapeutic targets. The challenge of this promising research tool is also discussed.