Head and neck cancer continues to present a major therapeutic challenge to physicians. Recent advances in molecular or gene therapy have allowed us to reassess these malignancies and consider novel strategies for their management. Since the first clinical trial 5 years ago, it has become apparent that gene transfer is no longer a speculative approach for treating malignancies. Gene therapy involves the introduction of genetic material (DNA) into host cells to induce the expression of the therapeutic product of that gene. This review summarizes the most recent data concerning the use of gene therapy as a treatment strategy for head and neck solid malignancies. A brief overview of the basic concepts of gene therapy as well as future potential applications is also discussed.