Although traditional chemotherapy has yielded disappointing results in the therapy of progressive metastatic thyroid cancer, the recent development of a wide range of novel therapies targeting critical steps in the pathogenesis of thyroid cancer has led to a renewed interest in thyroid cancer clinical trials. This review provides an overview of the pathogenesis of thyroid cancer with particular emphasis on specific molecular targets that can be modulated with these novel agents. The article reviews the results for the small number of thyroid cancer patients included in published therapeutic trials and critically examines patient selection criteria for inclusion in clinical trials. Given the dramatic increase in availability of thyroid cancer clinical trials, all patients with radioactive iodine-refractory, progressive metastatic thyroid cancer should be considered for inclusion in a novel therapy trial.