Surgical resection will cure only 15% to 20% of patients with seemingly localized esophageal cancer. Multimodality therapy has the potential to increase the cure rate by improving locoregional control and preventing systemic relapse. Randomized trials demonstrate that chemoradiation followed by surgery decreases local relapse as compared with surgery alone; however, the effect on overall survival remains uncertain. The additional impact of surgery following chemoradiation also remains unclear, with two randomized trials demonstrating an improvement in locoregional control without a benefit in survival. Morbidity and mortality of trimodality therapy have limited potential gains. Incorporation of docetaxel, irinotecan, and oxaliplatin into chemotherapy regimens prior to chemoradiation or as adjuvant therapy may decrease systemic recurrence. New radiation sensitizers may improve locoregional control. Biologic agents, such as cetuximab, trastuzumab, erlotinib, and bevacizumab, may enhance chemoradiation and target systemic micrometastases. Advances in radiation oncology and surgery may decrease morbidity and mortality from trimodality therapy, improving patient outcome.