The incidence of head and neck cancer continues to increase worldwide, with tobacco exposure and human papillomavirus type 16 infections being the major etiological factors. Current therapeutic options are ineffective in approximately half of the individuals afflicted with this malignancy. Developments in the identification of molecules that sustain head and neck squamous cell carcinoma (HNSCC) growth and survival have made molecular targeting by gene therapy approaches a feasible therapeutic strategy. Although gene therapy was originally designed to correct single gene defects, it has now evolved to encompass all forms of therapeutic interventions involving engineered cells and nucleic acids that modify the overall pattern of gene expression within target tissues. Several preclinical studies and clinical trials have tested the efficacy of targeting specific molecules in patients with HNSCC, using genetic therapy approaches. This review discusses promising preclinical and clinical approaches and new directions for HNSCC gene therapy.