Gastrointestinal (GI) cancer continues to be a leading cause of cancer morbidity and mortality worldwide. Over the past decade the treatment options for patients with GI cancers have increased with the advent of newer combination chemotherapy regimes. Despite these clinical advances, new strategies are warranted in order to improve the efficacy as well as the safety. New molecular targets have provided novel opportunities in the treatment of GI cancer. One of the most advanced new approaches to date is the use of targeted inhibitors of the epidermal growth factor receptor (EGFR). In this review we describe the current status of therapeutic strategies based on EGFR inhibitors in the treatment of GI cancer.