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Epidermal growth factor receptor (EGFR) signaling pathways play a key role in the regulation of cell proliferation, survival and differentiation. As a consequence, EGFR is one of the best studied ligand–receptor system and specific EGFR inhibition approaches are currently among the most promising and the most advanced in the clinical setting. Monoclonal antibodies (mAbs) and specific tyrosine kinase inhibitors (TKIs) have been developed, among which C225 (Cetuximab) and ZD1839 (Iressa), respectively, are the most advanced. The aim of the present review was not to cover the field of EGFR inhibitors, but to compare at experimental and clinical levels the different key points governing the actions of mAbs and TKIs. In addition, combinations of conventional chemotherapies with EGFR targeting drugs, as well as resistance mechanisms of EGFR targeting, have been reviewed.