The epidermal growth factor receptor (EGFR) is a transmembrane tyrosine kinase receptor involved in the proliferation and survival of cancer cells. EGFR is the first molecular target against which monoclonal antibodies (mAb) have been developed for cancer therapy. Here we review the mechanisms underlying the effects of EGFR-specific mAb in cancer therapy. The efficacy of EGFR-specific mAb in cancer occurs thanks to inhibition of EGFR-generated signalling; furthermore, the effects of antibodies on the immune system seem to play an important role in determining the overall anti-tumour response. In this review, attention is focused on cetuximab and panitumumab, two mAb introduced recently into clinical practice for treatment of metastatic colorectal and head and neck cancer which target the external part of EGFR.