Thyroid cancer is the most common malignant cancer of the endocrine system. Treatment for well differentiated forms include surgery and radioactive iodine ablation. When cancer cells exhibit a less differentiated phenotype they may no longer be able to accumulate iodine, making 131-I administration ineffective. Recent studies have demonstrated the important role of therapeutic agents that have redifferentiating potential, leading to reactivation and expression of thyrocyte-specific genes, including those responsible for iodine uptake. This review will discuss the results of the most recent studies on drugs with redifferentiating properties and their application in patients with radioiodine refractory thyroid cancer.