Despite marked advances in surgical therapy for patients with esophageal, esophagogastric, and gastric cancers, the overall prognosis of these patients has not markedly improved during the past decades. Multidisciplinary approaches using adjuvant postoperative and neoadjuvant preoperative therapeutic principles have received increasing attention with regard to the management of these patients. A series of randomized, prospective trials has demonstrated that adjuvant postoperative radiation or chemotherapy does not result in a convincing survival advantage after complete tumor resection in esophageal, esophagogastric junction, or gastric cancer. The available data on the role of neoadjuvant preoperative therapy are not yet conclusive. Although neoadjuvant therapy may reduce the tumor mass in many patients, several randomized, controlled trials have shown that, compared with primary resection, a multimodal approach does not result in a survival benefit in patients with locoregional, that is, potentially resectable, tumors. In contrast, in patients with locally advanced tumors, that is, patients in whom complete tumor removal with primary surgery seems unlikely, neoadjuvant therapy increases the likelihood of complete tumor resection on subsequent surgery, but only patients with objective histopathologic response to preoperative therapy seem to benefit from this approach. Consequently, in the future, improvements in the overall survival of patients with esophageal, esophagogastric junction, or gastric cancer most likely will be achieved only by tailored therapeutic strategies that are based on the individual tumor location, tumor stage, and consideration of established prognostic factors. A clear classification of the underlying tumor entity, a profound knowledge of the prognostic factors applicable, a thorough preoperative staging, and identification of parameters that allow for the prediction of response to preoperative therapy will become essential for the selection of the optimal therapeutic modality for individual patients.