Because of the poor prognosis for patients with locally advanced and metastatic esophageal, gastroesophageal junction and gastric cancers, increasing attention has focused on the integration of targeted agents into current therapies. The molecular targets of these agents include epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF) or its receptor, cyclooxygenase-2 (COX-2), mammalian target of rapamycin (mTOR) and components and regulators of the cell cycle. In this review article, we briefly discuss pre-clinical data and the rationale for targeting these pathways and summarize the results of clinical trials to-date, including completed and ongoing phase III evaluations.