Through clearly identified molecular mechanisms, EGFR targeting leads to cell physiology modifications as cell proliferation, apoptosis and DNA repair. These mechanisms can explain the proper activity of EGFR targeting drugs but also represent a strong rational basis on which several experimental studies have been designed with combinations of EGFR targeting and cytotoxic agents (chemotherapeutic drugs and radiotherapy). These data led to the development of clinical trials combining EGFR targeting agents and anticancer drugs. There is however a lack of experimental data concerning the importance of the drug sequences and above all the impact of EGFR tumoral expression on the effects of combinations. The lack of knowledge on resistance mechanisms to EGFR targeting is also a difficulty for an optimal development of EGFR targeting in the clinics.