Despite some advances in the past few years, the search for effective treatment modalities for advanced gastric and gastro-esophageal junction cancer is far from over. Available data clearly demonstrate that the development of new drugs will have little, if any, chance of success if it is not guided by in-depth knowledge of disease biology. However, using biologic agents to target key molecular pathways, such as those regulated by human epidermal growth factor receptor (HER) family members, may be effective. Indeed, the positive results achieved by the anti-HER2 agent trastuzumab in a phase III trial in HER2-positive patients support this approach. Many new anti-HER molecules are now under evaluation for the treatment of gastric and gastro-esophageal junction cancer, but so far attempts to identify reliable predictive factors from phase I and II trials have produced inconclusive results. In addition, large phase III trials are still being conducted in molecularly unselected populations. Refining patient selection is essential to maximize the benefit of targeted agents, to avoid significant toxicities and for the development of alternative therapeutic approaches in patients who have nonresponsive disease.