Although the extended RAS analysis allows a better identification of patients potentially candidates to anti-EGFR monoclonal antibodies, a significant proportion of tumours may still reveals refractory to such a treatment approach. In these latter cases patients are then exposed to unnecessary toxicities without clinical benefit. Among many further biological factors that may have a role in determining resistance/sensitivity to EGFR-inhibitors, the EGFR itself, other members of the HER family (i.e. HER-2 and HER-3) as well as other surface receptors such as the IGF-1 receptor seem of particular interest. Preclinical models have shown that these receptors are biologically connected to each other and able to directly or indirectly influence the downstream molecular pathways. In the presence of abnormal expression of these biological determinants, intracellular pathways may become independent from the receptor-targeting treatment thus making therapies directed against the receptor ineffective. Clinical observations and translational studies seem to confirm these findings. The Authors have reviewed the literature and have selected recent clinical reports focusing on translational research on the EGFR itself or on other molecules that may interfere with this pathway. We also discuss potential future developments in this area.