Oesophageal cancer is the sixth cause of cancer-related death worldwide. Nowadays radiochemotherapy (RTCT) plays a central role in the treatment settings of such disease. Evaluation of molecular targeted therapies is an attractive opportunity for the management of oesophageal, GEJ and gastric cancers to improve outcomes as happened for other primary tumours. Clinical trials focused on the potential of many molecular targeted agents included in CT schedules, but also on the possibility, efficacy and tolerance of their use combined with RT. This review will focus on the over 15 more promising agents studied in combination with RT for esophagogastric tumour, describing the mechanism and target of action, evidences and potential future role on over 50 trials evaluated. Mechanisms of action, studies and evidences about Human Epidermal Growth Factor type 2 Targeting Agents (one of the more promising), Epidermal Growth Factor's Receptor Inhibitors (nowadays showing a lower potential than expected), Vascular Endothelial Growth Factor Inhibitors, Mesenchymal Epithelial Transition Factor, Hepatocyte Growth Factor and other targeting agents are reviewed.