Esophageal cancer (EC) and gastric cancer (GC) constitute a major cause of cancer deaths worldwide. Recent improvements in both surgical techniques and adjuvant/neoadjuvant radiotherapy and chemotherapy approaches have increased the survival of patients with loco-regional disease. However, most of the patients with GC or EC have advanced disease either at diagnosis or at follow-up. Despite recent advances in the treatment of advanced disease, these patients still do poorly. An emerging understanding of the molecular pathways that characterize cell growth, cell cycle, apoptosis, angiogenesis and invasion has provided novel targets in cancer therapy. In this review we describe the current status of targeted therapies in the treatment of EC and GC. These therapeutic strategies include EGFR inhibitors, antiangiogenic agents, cell cycle inhibitors, apoptosis promoters and matrix metalloproteinases inhibitors. The emerging data from the clinical development of these compounds has provided novel opportunities in the treatment of EC and GC that will probably translate into efficacy advantage in the treatment of these common malignancies.