Epidermal growth factor receptor (EGFR) signalling has previously been identified as an important prognostic factor in patients with head and neck cancer (HNC). EGFR has been confirmed in a phase III randomized trial as a critical target in combination with radiation therapy for locally advanced HNC patients. Provocatively, the outcomes, at first glance, appear similar to patients treated with conventional chemo-radiation; but with less mucosal toxicity. Promising options for EGFR inhibition include targeting the epidermal growth factor receptor (EGFR) with tyrosine kinase inhibitors (EGFR-TKIs), and monoclonal antibodies to prevent ligand binding. There are limitations to EGFR inhibition as only 10% of patients respond to EGFR blockade with advanced disease; therefore, immunohistochemistry, fluorescence in situ hybridization (FISH), gene arrays and molecular analysis techniques have been performed in an effort to predict which patients will respond to EGFR targeted therapies. Are there new issues and discoveries regarding EGFR biology that will provide information to determine at the outset, which patients will respond to this type of therapy, and which patients will benefit from alternative “ targeted agents ” ? In development are agents that target selective parts of the EGFR pathway such as Akt, mTor or Src kinase inhibitors. Novel drugs attacking both the EGFR and angiogenic pathways may provide wider applicability and improve radiation response further. This review will update head and neck specialists as to relevant new information regarding EGFR inhibition, alternative approaches with targeted agents and challenges facing oncology investigators to better define the appropriate patient population to benefit from these new agents.