Current development of targeted therapy in oncology is particularly active and concerns principally two types of agents which are monoclonal antibodies (Mabs) and tyrosine kinase inhibitors (TKIs). Epidermal growth factor receptor (EGFR) signaling pathways play a key role in the regulation of cell proliferation, survival and differentiation. Consequently, EGFR is one of the most-studied ligand-receptor systems and specific EGFR inhibition approaches are currently among the most promising and the most advanced in the clinical setting. Cetuximab (Erbitux), belonging to the Mabs family, gefitinib (Iressa) and erlotinib (Tarceva), belonging to the TKIs family, are among the most advanced anti-EGFR drugs at the clinical level. The aim of this review article is to compare at both experimental and clinical levels the key points which govern the activity of these two types of targeting agents.