The semi-synthetic derivative of camptothecin, irinotecan, is active in esophageal adenocarcinoma, both alone and in combination with cisplatin. Use as front-line therapy in both multi-modality regimens and combination chemotherapy is common. More recently, the elucidation of the role of the epidermal growth factor receptor (EGFR) pathway in esophageal cancer has resulted in the pre-clinical and clinical study of the activity of EGFR directed agents for treatment of esophageal cancer.