Esophageal cancer is a highly lethal disease, with most patients presenting with unresectable or metastatic disease. Since metastatic esophageal cancer is an incurable disease, the goals for chemotherapy are to palliate symptoms and improve survival. Although some patients may achieve symptomatic improvement with the use of standard first-line chemotherapy regimens, response rates are usually low and short lasting. Virtually all patients with metastatic esophageal cancer will develop progressive disease following front-line therapy. With the availability of several chemotherapeutic agents with more tolerable side effects, a number of patients who retain a good performance status after the initial treatment remain candidates for additional therapy. This review summarizes the recent advances in second-line therapy for esophageal cancer.