High expression levels of epidermal growth factor receptor (EGFR) have been frequently observed in many malignancies; and it is implicated in aggressive biological behaviors of tumor cells and poorer prognosis of tumor patients. Evaluation of EGFR as therapeutic target for cancer is highly warranted. The EGFR-targeted antitumor approaches have been extensively studied over the past decades, including passive immunization with monoclonal antibody and small molecular weight kinase inhibitor of EGFR. These approaches showed promising antitumor potential at pre-clinical studies and clinical trials. A number of mechanisms were thought to play a role in the induced tumoricidal responses, including:(1)arrest of cell cycle; (2)up-regulation of pro-apoptotic molecules; (3)anti-angiogenesis; (4)inhibition of invasion and metastasis of tumor; (5)sensitization of tumor cell to chemotherapy and radiotherapy. In addition, we have proposed a model to break immune tolerance against self-EGFR by immunization with an altered immunogen based on xenogeneic homologous molecule. We found that human EGFR as an immunogen could induce specific immune responses in mice, which also cross-reacts with mouse EGFR and results in antitumor immunity against EGFR-positive malignancies. In general, no marked EGFR-related side effects were found in all EGFR targeted therapeutics. This would be partly explained by significant down-regulation of EGFR and limited dependence on EGFR signal transduction in normal cells.