The mortality associated with head and neck cancer has remained largely unchanged for the past several decades despite advancements in surgery, radiotherapy and chemotherapy. Gene therapy is a novel treatment approach that may potentially advance the treatment of genetic diseases, which include malignancies such as head and neck cancer. Multiple vector systems have been developed that facilitate the introduction of therapeutic genetic material into cells. These include DNA-based vectors, viral vectors and, most recently, vectors that induce RNA interference. Gene therapy strategies can be classified in 3 groups: (1) cytoreductive therapy aimed at directly inducing cell death, (2) corrective therapy intended to repair genetic defects underlying malignancy, and (3) immune modulation to promote a robust immune response against cancer. Cells. Translational research has been conducted in each of these areas, culminating in clinical trials and the implementation of gene therapy as a viable therapeutic modality for head and neck cancers.