Gastric cancer is the second leading cause of cancer mortality in the world and its management, especially in advanced stages, has evolved relatively little. In particular, no targeted modality has so far been incorporated to its treatment armamentarium. HER2 overexpression is increasingly recognized as a frequent molecular abnormality, driven as in breast cancer by gene amplification. There is mounting evidence of the role of HER2 overexpression in patients with gastric cancer, and it has been solidly correlated to poor outcomes and a more aggressive disease. Additionally, preclinical data are showing significant antitumor efficacy of anti-HER2 therapies (particularly monoclonal antibodies directed towards the protein) in in vitro and in vivo models of gastric cancer. As a result, several clinical trials are exploring in different settings and with diverse designs the potential of anti-HER2 therapies in gastric cancer patients. This review summarizes the rationale, preclinical evidence, retrospective clinical analyses, and the interim clinical data pertaining HER2 therapies in gastric cancer.