Adjuvant and neoadjuvant therapeutic principles have in recent years received increasing attention in the management of patients with esophageal cancer. A series of randomized prospective trials has convincingly demonstrated that adjuvant postoperative radiation or chemotherapy does not result in a survival advantage after a complete tumor resection. The available data on the role of neoadjuvant preoperative therapy in patients with adenocarcinoma or squamous cell carcinoma of the esophagus are not yet conclusive. While neoadjuvant therapy may undoubtedly reduce the tumor mass in a substantial portion of patients, a series of randomized controlled trials has shown that compared with primary resection, a multimodal approach does not result in a survival benefit in patients with locoregional, i.e., potentially resectable, tumors. In contrast, in patients with locally advanced tumors, i.e., tumors in which a complete tumor removal with primary surgery appears unlikely, neoadjuvant therapy allows a marked downstaging of the primary tumor and thus significantly increases the chance for complete tumor removal on subsequent surgery. However, only patients with objective clinical or histopathological response to preoperative therapy appear to benefit from this approach. Compared with preoperative chemotherapy alone, combined radiochemotherapy increases the rate of response but may also increase postoperative morbidity and mortality. Neoadjuvant therapy should therefore currently be performed only in experienced centers within the context of clinical trials. The identification of factors which would facilitate prediction of the response to neoadjuvant therapy is currently the focus of several studies. Furthermore, more effective and less toxic preoperative therapy regimens are required to increase the response rates and combat systemic recurrences.