Among the most promising new antineoplastic therapies for poorly differentiated or undifferentiated thyroid cancer are the histone deacetylase inhibitors and the peroxisome proliferator-activated receptor (PPAR)-gamma agonists. These two classes of drugs have been shown to inhibit growth and induce apoptosis and redifferentiation in a variety of hematologic and solid cancer cell lines and animal models. In this article we review the molecular mechanisms, in vitro and in vivo studies, and clinical applications of the histone deacetylase inhibitors and PPAR-gamma agonists in the treatment of thyroid cancer.