The epidermal growth factor receptor (EGFR) autocrine pathway plays a crucial role in human cancer since it contributes to a number of highly relevant processes in tumor development and progression, including cell proliferation, regulation of apoptotic cell death, angiogenesis and metastatic spread. Among a variety of approaches used to target EGFR signaling, EGFR blocking monoclonal antibodies and small molecular weight EGFR tyrosine kinase compounds have been successfully developed. The results of a large body of preclinical studies and clinical trials suggest that targeting the EGFR could represent a significant contribution to cancer therapy. Both types of agent exert a significant antiproliferative activity when used alone or in combination with conventional antitumor treatments, such as chemotherapy or radiation therapy. Although the advanced clinical development of EGFR blocking drugs demonstrates their efficacy in some human metastatic diseases, such as lung, head and neck and colorectal cancers, the issue of constitutive resistance in a large number of patients and the development of acquired resistance in the responders remains an unexplored subject of investigation. Recent evidence suggests the role of specific activating mutations within the tyrosine kinase domain of EGFR to explain the dramatic responses to small molecule tyrosine kinase inhibitors in a subgroup of lung cancer patients. However, the intrinsic molecular mechanisms of resistance to these drugs are still unclear. This review will focus on the preclinical findings on therapeutic resistance to EGFR targeting agents.