SUMMARY. Esophageal cancer is highly aggressive and is the sixth leading cause of cancer death worldwide. Recent advances in multimodality chemoradiotherapy and surgery has improved survival in patients with loco-regional disease, but most patients with advanced stage esophageal cancer have a poor prognosis. Elucidation of the processes involved in esophageal carcinogenesis has identified a number of promising novel targets for therapy. This review focuses on the current status of targeted therapies with potential application to the treatment of advanced esophageal and gastroesophageal junction cancer. The future challenge is to confirm the efficacy of these targeted agents in appropriately selected esophageal cancer patients, and successfully integrate these agents into effective therapies for all stages and subtypes of disease.