Head and neck squamous cell carcinoma is a clinically challenging disease that resulted in more than 500,000 cases worldwide in 2001. In the United States, head and neck squamous cell carcinoma has accounted for approximately 40,000 cases with 12,000 deaths reported in 2001, which makes it the fifth leading cause of cancer incidence and the sixth leading cause of cancer-related deaths. Patients with recurrent or metastatic disease have a median survival rate of approximately 6 months; and there is little evidence from randomized trials that survival advantages have been achieved over the community standard of cisplatin and infusional 5-fluorouracil combination. Despite significant improvements in diagnosis, local management, and chemotherapy of head and neck cancer, there has been no significant increase in long-term survival rates over the past 30 years. As little progress has been made, new management approaches are required. Novel biologic agents have been developed to target multiple specific regions of the cancer cell. Epidermal growth factor receptor blockers have been investigated, such as anti epidermal growth factor receptor monoclonal antibodies, tyrosine kinase inhibitors, ligand conjugates, immunoconjugates, and antisense oligonucleotides. Farnesyl transferase inhibitors are a class of compounds that inhibit a critical enzymatic step in the constitutive expression of mutated ras genes, which are present in more than 27% of oral cancers. Strategies targeting the p53 gene and protein may halt or reverse the process of tumorigenesis and metastasis as p53 mutations occur in 45 to 70% of head and neck squamous cell carcinoma patients. Continued development of these novel agents may help improve the overall response and survival rate of patients with head and neck cancer.