Head and neck cancer, because of its anatomic accessibility and poor overall survival rate, has become a frequent target of novel gene therapy intervention strategies. Viral and nonviral vectors have been used to transfer a variety of tumor suppressor genes, suicide genes, and immunologic genes into head and neck cancer cells in both the laboratory and clinical setting. Gene therapy as an isolated treatment modality will probably not replace standard treatment modalities in the management of head and neck cancer. It seems likely, however, that gene transfer will find its way into the multidisciplinary care of the head and neck cancer patient, where novel treatments are combined with standard therapies in order to maximize tumor response.