The epidermal growth factor receptor (EGFR) has been the focus of much attention in the age of targeted cancer therapeutics. In addition to its role in signal transduction under physiological conditions, it has been of interest because it is highly expressed in many tumor types and influences growth and survival in malignant states. Advances in the understanding of the EGFR and in genetic engineering have led to the development of monoclonal antibodies targeting the extracellular domain of the membrane-bound receptor. Cetuximab and panitumumab are the two most advanced such compounds. Thus far, cetuximab has achieved regulatory approval in metastatic colorectal cancer, and locally advanced and metastatic squamous cell cancer of the head and neck; panitumumab has been approved for metastatic colorectal cancer. This review will focus on the EGFR signaling network, monoclonal antibodies against EGFR and the pertinent clinical trials in this field of oncology using such agents.