The epidermal growth factor receptor (EGFR) is a transmembrane receptor with tyrosine kinase activity involved in regulation of cellular multiplication, survival, differentiation and metastasis. Our knowledge about function and complex management of these receptors has driving the development of specific and targeted treatment modalities for human cancers in the last 20 years. EGFR is the first receptor target against which monoclonal antibodies (mAb) have been evolved for cancer treatment. Here we review the biology of ErbB receptors, including their architecture, signaling, regulation and therapeutic strategies and the mechanisms of resistances offered by the receptors against small-molecule tyrosine kinases and resistance overcome implications of mAbs. The efficacy of EGFR-specific mAb in cancer depends on site specific extracellular region of EGFR, which has crucial role in process of dimerization and activation. This review highlights evolution of various resistance mechanisms due to consequences of current small-molecule anti-EGFR therapies.