Surgical resection has been traditionally the mainstay of treatment for localized esophageal cancers. However, survival after surgery alone for advanced esophageal cancer is not satisfactory. In Japan, the development of multimodal therapy for esophageal cancers has centered mainly on systemic chemotherapy plus surgery to control distant metastasis. Based on the results of the recent Japan Clinical Oncology Group (JCOG) 9907 study, preoperative chemotherapy (consisting of 5-FU and cisplatin) followed by surgery has emerged as the standard treatment. In Western countries, where chemoradiotherapy followed by surgery has been mainly explored for patients with resectable esophageal cancers, two large controlled trials that evaluated the effectiveness of preoperative chemotherapy reported conflicting results. However, a recent meta-analysis reported significant survival benefits for preoperative chemotherapy in patients with adenocarcinoma of the esophagus. We need to find new effective preoperative chemotherapeutic regimens, including molecular target agents, with response rates higher than that of the conventional chemotherapy of 5-FU and cisplatin. However, we also must compare the survival benefits of preoperative chemotherapy with preoperative chemoradiotherapy.