Despite improvements in surgical techniques and perioperative management and surgery combined with chemotherapy and/or radiotherapy, the prognosis of esophageal squamous cell carcinoma (SCC) at an advanced stage remains poor. Therefore, for esophageal SCC patients, novel therapies such as small molecule inhibitors of tyrosine kinases (TKIs) and humanized monoclonal antibodies (mAbs) are very much needed.Esophageal SCC shows a relatively high incidence of EGFR (33%) and/or HER2(31%) overexpression. Two categories of anti-HER-family-targeting therapies have been in clinical development: small-molecule, HER-family-related TKIs such as Gefitinib,Erlotinib and Lapatinib, and humanized mAbs against the HER family represented by Cetuximab and Trastuzumab. Although there have been very few clinical trials of antiHER-family targeting drugs in esophageal SCC, some in vitro data suggested that the combination of Cetuximab and Trastuzumab could induce synergistic antiproliferative effects and additional antibody-dependent cellular cytotoxicity (ADCC) activities against esophageal SCC cells. A better understanding of the detailed mechanisms involved in EGFR and/or HER2 may help identify new therapeutic targets in esophageal SCC.