This article examines the role of combined-modality therapy for treating locally advanced esophageal cancer. Although surgery remains a cornerstone of treatment, recent studies have demonstrated that pre- or perioperative chemotherapy is associated with improved survival for patients who have adenocarcinoma histology. Primary chemoradiotherapy is the accepted standard of care for medically inoperable patients. Recent studies also suggest that definitive chemoradiotherapy is acceptable for patients who have squamous histology, while subsequent surgery improves local control without conferring a clear survival benefit. Neoadjuvant chemoradiotherapy continues to be investigated but is associated with several advantages over neoadjuvant chemotherapy alone, including an improvement in the pathologic complete response rate and resectability. Patients who achieve a pathologic complete response also appear to have improved survival. Adjuvant chemoradiotherapy may be considered for patients who undergo primary resection of lower esophageal/gastroesophageal junction adenocarcinoma.