Esophageal cancer, though relatively uncommon in the United States, is a major global health threat. Squamous cell carcinoma remains the most common histology worldwide, whereas adenocarcinoma of the esophagus is increasing at epidemic proportions in the United States and other Western countries. Both histologies carry a poor prognosis: 5-year mortality for esophageal cancer exceeds 85% to 90%. Locally advanced esophageal cancer treated with the standard approaches of surgery or radiotherapy is associated with poor prognosis, due to both a high incidence of local-regional treatment failure and early systemic dissemination of disease. The obvious need to address the early spread of esophageal carcinoma through systemic treatment has led to the study of combined-modality therapies incorporating chemotherapy. Concurrent chemotherapy and radiotherapy is now a standard of care in the nonsurgical management of locally advanced esophageal cancer. Preoperative chemotherapy and combined preoperative chemoradiotherapy are also standards of treatment based on recent clinical trials. With the increasing use of chemotherapy as part of operative management as well, systemic chemotherapy will ultimately be used to treat the majority of patients with esophageal cancer. This article reviews results of recent clinical trials in the use of single-agent chemotherapy, combination chemotherapy, targeted agents, and neoadjuvant chemotherapy in the treatment of esophageal cancer.