Despite advances in surgery, radiotherapy, and the incorporation of novel systemic agents into treatment, long-term outcomes of patients with head and neck cancer remain unsatisfactory. The growing understanding of head and neck cancer biology suggests that targeting molecular events governing carcinogenesis or tumor progression may provide novel therapeutic approaches for head and neck cancer. Squamous cell carcinoma of the head and neck (SCCHN) is characterized by locoregional spread and is clinically accessible, making it an attractive target for intratumoral gene therapy, a potentially efficacious experimental treatment. Systemic delivery of gene therapy may be also possible, albeit with several limitations. In this review we will discuss the rationale, delivery methods, and accumulated clinical data with cancer gene therapy in SCCHN.