Molecular targeted therapy is already becoming indispensable in the field of cancer chemotherapy. Molecular target drugs with different mechanisms of action in comparison to cytotoxic agents, and with no overlapping adverse events, are expected to become a potential breakthrough treatment alternative. The same effect was expected for radiotherapy and the additive effect of cetuximab, which is an anti-EGFR antibody over radiation monotherapy, has been demonstrated in locally advanced head and neck cancer. Since EGFR is highly expressed (50%–70%), and the KRAS mutation is infrequent (5%) in esophageal cancer, such anti-EGFR therapy is therefore expected to improve the efficacy of esophageal cancer therapy. Many phase II studies have so far been conducted using anti-EGFR agents, such as cetuximab, gefitinib, erlotinib and panitumumab concurrently with conventional chemoradiothearpy. A phase III trial (RTOG0436) which evaluates the additive effect of cetuximab on paclitaxel plus cisplatin that is administered concurrently with radiation (50.4 Gy) is now in progress. Another anti-EGFR monoclonal antibody, nimotuzumab, is also presently being evaluated for its safety and efficacy in a phase I study of cases receiving combined treatment with 5-FU, cisplatin and radiation in Japan. Furthermore, a phase III trial (RTOG1010) evaluating the additive effect of trastuzumab to the trimodality treatment regimen of Her2-overexpressing esophageal adenocarcinoma has also recently been started. The survival benefits of each molecular targeting drug should therefore be evaluated in a randomized phase III trial. Although global or regional pivotal trials are still needed for esophageal cancer, the regional differences in drug effectiveness or histology of cancer should be carefully taken into consideration.