Esophagogastric cancer represents a significant global health problem, with most patients presenting with advanced-stage disease and consequently with a poor prognosis. Chemotherapy improves survival compared with supportive care alone, and combination chemotherapy regimens are more effective than monotherapy. Overexpression of EGFR and possibly HER2 confer a poor prognosis, providing potentially important therapeutic targets for selected patients. Inhibition of HER2 with the monoclonal antibody trastuzumab in patients with HER2 overexpression, HER2 gene amplification, or both, is effective and has been the standard of care for HER2-positive breast cancer for almost a decade. In patients with advanced-stage gastric or esophagogastric-junction adenocarcinomas, the addition of trastuzumab to a cisplatin plus fluoropyrimidine doublet was reported to improve response rate, progression-free survival and overall survival, with the greatest benefit reported in the subgroup of patients with the highest expression of HER2. Cetuximab and panitumumab, two monoclonal antibodies against EGFR, and the dual EGFR and HER2 tyrosine kinase inhibitor lapatinib are currently undergoing phase III evaluation in esophagogastric cancer. We discuss the preclinical rationale for targeting human EGFRs and recent clinical reports of these targeted agents in esophagogastric cancer.