Although most thyroid cancers may be cured by surgery and 131I therapy, approximately 10–20% of patients die from advanced differentiated and anaplastic tumors that are unresponsive to conventional treatments. Thus, alternative approaches such as gene therapy are of interest, especially using targeted therapeutic gene delivery. Several strategies have been designed specifically for thyroid cancer and some have proven to be feasible in preclinical studies. In particular, it is suggested that combined gene therapy approaches, as well as multimodality therapeutic regimens, including gene therapy and conventional treatments, should be pursued to achieve clinically significant results. The recent discovery of new markers of thyroid cancer should improve the efficacy of gene therapy.