Cancer of the esophagus is an aggressive disease with early lymphatic and hematogenous dissemination and at present often considered as one clinical entity because of their comparable increasing incidence, prognosis and optimal treatment options. However, it is still a matter of debate whether these malignancies have the same pathogenesis and genotype. Despite recent advances, treatment of upper gastrointestinal malignancies remains a significant challenge. Molecular pathology has revealed many molecular mechanisms of disease progression, which are related to prognosis. Better knowledge of molecular bases may lead to new paradigms, improved prognostication, early diagnosis and individually tailored therapeutic options. This review summarizes the rationale, preclinical evidence, retrospective clinical analyses and the interim clinical data pertaining HER2 therapy and many other molecular pathways.