Radiation therapy as single or combined modality (concurrent chemoradiotherapy) has been the cornerstone of treatment for squamous cell carcinoma of the head and neck for a long time. Fortunately, advances in tumor biology have provided new insights of tumor proliferation, metastases, migration and cell cycle regulation. The success seen with the use of cetuximab alone or in combination with conventional treatments has led the roadmap to discover other potential target mechanisms which may translate into better response rate with less local and systemic toxicity and improved overall survival. In this review, we discuss other cellular pathways that have shown to be involved in the carcinogenesis of squamous cell carcinoma of the head and neck and the actual efforts to target these mechanisms.