Esophageal cancer (EC) is an aggressive cancer and is a leading cause of cancer-related death worldwide. In the United States and Western Europe, there has been a decline in the incidence of squamous cell carcinomas coupled with a rapid rise in incidence of adenocarcinoma of the esophagus and gastroesophageal junction. Although the 5-year survival rates have slowly increased over time from 4% to 14%, the outcomes are still dismal. The lack of adequate preventative strategies, inadequate screening techniques, early lymphatic and hematogenous spread, and lack of truly effective therapeutic agents all contribute to the poor outcome. This review will highlight the current status of targeted therapies in EC. This will include a review of agents targeting the vascular endothelial growth factor and epidermal growth factor receptor pathways and trials planned or ongoing to incorporate these and other agents into therapy for advanced disease and into combined modality therapy for early-stage tumors. Further work is required regarding the rational integration of these targeted agents and the optimal selection of patients who will most likely benefit.