Attempts to improve results of chemoradiotherapy by increasing the total dose of radiation or chemotherapy or by changing chemotherapeutic drugs have not been very successful. Additionally, some combinations have been associated with a high rate of unacceptable treatment-related morbidity, underscoring the need for new treatment strategies to combine with radiation to improve the therapeutic ratio. Potentially useful strategies include the selective protection of normal tissues, interference with resistance mechanisms, improved targeting of tumor stem cells, and dealing with residual tumor disease. Evidence is mounting that epidermal growth factor receptor (EGFR) overexpression or mutation, as well as dysregulation in cyclins and cyclin-dependent kinases represent major determinants in aggressive tumor growth and poor tumor response to standard treatment modalities, including radiotherapy. Two major approaches have been investigated, one consisting of blocking the extracellular domain of the receptor with anti-EGFR antibodies to prevent ligand-receptor binding, and the other consisting of small chemical compounds, tyrosine kinase inhibitors, which bind to the intracellular domain of the receptor preventing its phosphorylation. Clinical trials are evaluating whether or not quantifying EGFR expression in tumors can serve as a predictor of treatment outcome and if the incorporation of EGFR inhibitors into radiotherapy can improve treatment outcome.