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Metastatic esophageal cancer is incurable with 5-year survival rates of under 5% using currently available therapeutic strategies. Palliative chemotherapy with cisplatin- and 5-fluorouracil (5FU)-based regimens remains the standard of care for patients with recurrent unresectable or metastatic esophageal cancer. Upfront cisplatin-based regimens are poorly tolerated in some patient groups and, for patients with recurrent disease after platinum-based therapies, there is a need for an alternate efficacious regimen without significant toxicities. The combination of docetaxel and irinotecan is an active regimen in this disease and has been investigated in several phase II trials. Weekly dosing of chemotherapy is preferred over a once every 3 weeks regimen on account of comparable efficacy and improved toxicity profile. Future directions include investigation of pharmacogenomic treatment assignment, particularly as irinotecan appears to be active in tumors with high ERCC1 expression, which tend to be resistant to cisplatin. Combinations with biologics such as bevacizumab and cetuximab, which have shown additive benefit with other cytotoxic combinations, are also of interest for future study. [ABSTRACT FROM AUTHOR]