The incidence of esophageal cancer continues to increase due to a rapid increase in adenocarcinoma of the distal esophagus and gastroesophageal junction. At least 50% of patients present with metastatic cancer and most patients with localized disease will develop metastases despite potentially curative local therapy. Thus, the majority of esophageal cancer patients will become candidates for palliative chemotherapy. Traditionally, single agents effective in this disease have included cisplatin, 5-fluorouracil, and mitomycin. The combination of cisplatin and continuous-infusion 5-fluorouracil is the standard for both squamous cell carcinoma and adenocarcinoma, with a 25% to 35% response rate in metastatic disease. More recently, paclitaxel has shown favorable results as a single agent or in combination with cisplatin in both disease histologies. One-hour weekly paclitaxel, a promising schedule with little toxicity, is under active investigation. Weekly irinotecan and cisplatin is a highly effective new regimen in both adenocarcinoma and squamous cell carcinoma with relatively little toxicity. Vinorelbine has demonstrated response in squamous cell carcinoma and has less toxicity than its predecessor, vindesine. Use of newer agents in combination with concurrent radiotherapy in locally advanced disease is the subject of ongoing clinical trials.