In spite of the overexpression and efficient inhibition of epidermal growth factor receptor (EGFR), resistance to EGFR inhibitors, monoclonal antibodies and tyrosine kinase inhibitors may occur. Understanding the molecular mechanisms affecting cancer cell sensitivity or resistance to EGFR inhibitors may be of help in deciding on treatment and in new translational studies. This review will focus on the most relevant mechanisms contributing to the acquisition of sensitivity/resistance to EGFR inhibitors.