Esophageal adenocarcinoma is an aggressive malignancy with a poor outcome, and its incidence continues to rise at an alarming rate. Current treatment strategies combining chemotherapy, radiation, and surgery are plagued with high rates of recurrence and metastasis. Multiple molecular pathways including the epidermal growth factor receptor, vascular endothelial growth factor, v-erb-b2 erythroblastic leukemia viral oncogene homolog (ERBB2), and Aurora kinase pathways are activated in many esophageal adenocarcinomas. In many cases, these pathways have critical roles in tumor progression. Research on the mechanisms by which these pathways contribute to disease progression has resulted in numerous biologic agents and small molecules with the potential to improve outcome. The promise of targeted therapy and personalized medicine in improving the clinical outcome is now closer than it has ever been.