Epidermal growth factor receptor (EGFR), a member of the ErbB family (EGFR, ErbB2, ErbB3 and ErbB4), plays a crucial role in regulating various cellular responses such as proliferation, differentiation and survival. As a result, aberrant activation of EGFR, which is mostly mediated through different classes of genomic alterations occurring within EGFR, is closely associated with the pathogenesis of numerous human cancers including lung adenocarcinoma, glioblastoma and colorectal cancer. Therefore, specific suppression of oncogenic activity of mutant EGFR with its targeted drugs has been routinely used in the clinic as a very effective anti-cancer strategy in treating a subset of tumors driven by such oncogenic EGFR mutants. However, the clinical efficacy of EGFR-targeted therapy does not last long due to several resistance mechanisms that emerge in the patients following the drug treatment. Thus, there is an urgent need for the development of novel therapeutic tactics specifically targeting mutant EGFR with the focus on the unique biological features of various mutant EGFR. In regards to this point, our review specifically emphasizes the recent findings about distinct requirements of receptor dimerization and autophosphorylation, which are critical steps for enzymatic activation of EGFR and signaling cascades, respectively, among wildtype and mutant EGFR and further discuss their clinical significance. In addition, molecular mechanisms regulating EGFR dimerization and enzymatic activity by a key negative feedback inhibitor Mig6 as well as the clinical utility for developing potential novel drugs targeting it is described in this review.