Worldwide more than a half million people develop Head and Neck cancer annually. Despite a significant decrease in smoking, about 40,000 new patients are diagnosed with carcinoma of the head and neck annually in the United States, and 11,000 of them succumb to their disease. More than 90% of these cancers are squamous cell carcinoma. The survival rates of patients with squamous cell carcinoma of the head and neck (SCCHN) have not improved significantly despite multimodality therapy including surgery, radiation therapy, and chemotherapy. Recently, molecular targeted agents have shown significant improvement in clinical outcomes in chronic myelogeneous leukemia with imatinib, breast cancer with trastuzumab, colon cancer with bevacizumab and cetuximab, and renal cell cancer with sorafenib and sunitinib. In SCCHN the epidermal growth factor receptor (EGFR) antibody cetuximab has shown promising results in a phase III trial in combination with radiation. How best to integrate these agents with the traditional treatment modalities of surgery, radiotherapy, and cytotoxic chemotherapy is of vital importance but has yet to be determined. This article will discuss the biology of molecular targeted agents as well as current clinical trials and future directions of these agents in SCCHN.