The epidermal growth factor receptor (EGFR) is responsible for the growth and progression of tumor cells; its overexpression and deregulation of its downstream signaling pathway have been found in many different neoplasms. These characteristics make it an ideal target for cancer treatment. Two classes of EGFR inhibitors, which bind to different parts of this molecule, have been developed and studied: monoclonal antibodies, such as cetuximab and panitumumab and tyrosine kinase inhibitors, including erlotinib and gefitinib. The effectiveness of these new drugs is considerably reduced by a number of mechanisms of resistance developed by tumor cells. Hence, there is a clear need for better characterization of these processes and finding new therapeutic strategies to make the action of these drugs more incisive. Here, we describe some of the mechanisms of resistance to EGFR inhibitors and review the main innovations attempting to overcome these drawbacks.