The epidermal growth factor receptor (EGFR) is a cellular transmembrane receptor with tyrosine kinase enzymatic activity which plays a key role in human cancer. EGFR-dependent signaling is involved in cancer cell proliferation, apoptosis, angiogenesis, invasion and metastasis. Targeting the EGFR is a valuable molecular approach in cancer therapy. Several anti-EGFR drugs are in Phase III clinical development as single agent or in combination with other anticancer modalities. Cetuximab (Erbitux), a chimeric human-mouse monoclonal immunoglobin (Ig)G1 antibody, which blocks ligand binding and functional activation of the EGFR, is currently registered in the USA, Switzerland and the European Union for the treatment of advanced, irinotecan-refractory colorectal cancer. Gefitinib, (Iressa), a small molecule EGFR-selective inhibitor of tyrosine kinase activity which blocks EGF autophosphorylation and activation, has been the first EGFR-targeting drug to be registered in 28 countries worldwide, including the USA, for the third-line treatment of chemoresistant non-small cell lung cancer patients. This review will focus on the preclinical background and on the clinical data with the anti-EGFR drugs in most advanced clinical development. Furthermore, a series of open clinical issues for the development of optimal strategies of using EGFR-targeting agents will be discussed.