In recent years, the epidermal growth factor receptor (EGFR) has been recognized as a central player and regulator of cancer cell proliferation, apoptosis and angiogenesis and, therefore, as a potentially relevant therapeutic target. Several strategies for EGFR targeting have been developed, the most succesful being represented by monoclonal antibodies, that directly interfere with ligand-receptor binding and small molecule tyrosine kinase inhibitors, that interfere with activation/phosphorylation of EGFR. These agents have been authorized in advanced chemorefractory cancers, including colorectal cancer, non-small-cell lung cancer and head and neck cancer. However, evidence of resistance to these drugs has been described and extensive studies have been performed to investigate whether resistance to EGFR-targeted therapy is primary or secondary. Cellular levels of EGFR do not always correlate with response to the EGFR inhibitors. Indeed, in spite of the over expression and efficient inhibition of EGFR, resistance to EGFR inhibitors may occur. Moreover, given the genetic instability of cancer cells, genetic modifications could enable them to acquire a resistant phenotype to anti-EGFR therapies. Taken together, these findings support the importance of understanding the molecular mechanisms affecting cancer cell sensitivity or resistance to such inhibitors. This review will focus on the most relevant mechanisms contributing to the acquisition of sensitivity/resistance to EGFR inhibitors.