Numerous cellular pathways have a significant impact in the growth and metastatic potential of tumors. Essential element of such pathways is the epidermal growth factor receptor (EGFR), a member of the HER family of receptor tyrosine kinases. One of the most important issues in cancer, which attracted the attention of clinical oncologists, is the potential use of targeted therapies. EGFR signaling pathway is implicated in the control of cell survival, proliferation, metastasis and angiogenesis. EGFR is, therefore, an appealing target for molecular-targeted cancer therapy as it is expressed in a variety of solid tumors (colorectal, breast, head and neck, etc.). Receptor antagonists that target EGFR have already been of high interest for a number of years. Multiple therapeutic strategies have been developed to target EGFR, including monoclonal antibodies (mAbs), tyrosine kinase inhibitors (TKIs), ligand-toxin conjugates, and antisense oligonucleotides. In particular, mAbs block ligand from binding to the extracellular domain of the receptor. Two mAbs that block EGFR (erbB1), cetuximab and panitumumab, have been approved by FDA. Cetuximab is a chimeric IgG1 anti-EGFR monoclonal antibody, whereas panitumumab is a fully human IgG2 anti-EGFR monoclonal antibody. This review highlights the cellular effects of EGFR blockade by mAbs and their relationship to therapeutic efficacy and biological significance.