Most patients with thyroid cancer have well differentiated tumors that usually respond to conventional therapy including total or near total thyroidectomy, radioiodine ablation and TSH suppression. About 10% of patients, however, have aggressive cancers as a consequence of de-differentiation. During de-differentiation, thyroid cancers not only show more mitosis, fibrosis, and altered cell structure, they also lose thyroid-specific functions (iodine uptake, TSH receptor expression, and thyroglobulin production). These poorly differentiated or undifferentiated tumors mostly fail to take up radioiodine and are responsible for most deaths from thyroid cancer. New therapies need to be developed for patients with these types of tumors. Among the most promising antineoplastic therapies for these poorly differentiated and undifferentiated thyroid cancers are the histone deacetylase inhibitors, the PPAR-gamma agonist and retinoic acids. These drugs have therapeutic effects for thyroid cancers in inhibiting growth and inducing apoptosis and redifferentiation, in vivo and in vitro studies. And, clinical trials in patients with refractory thyroid cancers have been initiated. Further laboratory investigation of these drugs is necessary to understand molecular mechanisms and demonstrate therapeutic efficacy for thyroid cancers.