Cumulative evidence indicates that epidermal growth factor receptor (EGFR) is one of the most commonly altered genes in human cancer, via overexpression, amplification and mutation. Targeted inhibition of EGFR activity suppresses signal transduction pathways which control tumor cell growth, proliferation and resistance to apoptosis. Small molecule tyrosine kinase inhibitors (TKIs) are among the most common EGFR-targeting agents and have been used clinically to treat various malignancies. This review discusses the mechanism of action and clinical data that are relevant to the use of EGFR-TKIs in the treatment of esophageal carcinoma. The clinical and basic scientific experience of these agents thus far have implications for the future of therapeutic targeting of EGFR.