The advent of multi-omic profiling of tumors, together with the increasing affordability of high-throughput drug screening programs, has helped usher in a new era of molecular targeted therapies for many solid malignancies. However, there has been limited success in esophageal adenocarcinoma. Until recently, preclinical drug development for this cancer has been largely limited to a small number of cell line models. Now, the increasing availability of patient-derived xenografts and novel metastatic models are helping to bridge the gap between scientific discovery and patient care. These platforms are valuable adjuncts for drug testing. Nevertheless, further work is required to develop systems that model the tumor microenvironment, including cancer cell interactions with the immune system, which will be particularly relevant for the translation of novel immunotherapies for esophageal adenocarcinoma.