The development of epidermal growth factor receptor (EGFR) inhibitors was greeted with tremendous enthusiasm in the therapy of squamous cell carcinoma of the head and neck (SCCHN) based on the nearly universal expression of this protein, the negative prognostic associations with expression, and robust preclinical data. Clinical trials to date have demonstrated modest activity of these drugs as single agents with reproducible major response rates of 5% to 15% in SCCHN depending on agent, dose, and schedule. The biology of responsiveness to these agents remains unclear, although an association of development of cutaneous toxicity with positive outcome has been reported repeatedly. Nevertheless, molecular markers of response or resistance have yet to be fully delineated. In the near future, phase III clinical trials will elucidate the role of these agents in second-line recurrent and/or metastatic (R/M) disease, the combination of EGFR inhibitors with other therapeutic strategies will be broadly advanced, and a set of molecular predictors of benefit will begin to emerge. This article will review the progress in utilization of EGFR inhibitors in R/M SCCHN.