Thyroid cancer is one of the most rapidly increasing cancers in many countries. Although most thyroid cancers are differentiated cancers and easily treated with radioiodine (RI), a portion of differentiated and undifferentiated cancers is refractory not only to RI therapy, but also to radiotherapy and chemotherapy. Thus, various alternative therapies have been tested in RI-refractory thyroid cancers. These alternative therapies include two major categories: redifferentiation therapy and recent molecular target therapy. Several clinical trials have investigated these therapies. They demonstrated potential effects of the therapies, although the results have been somewhat limited so far. Thus, the future strategy for undifferentiated thyroid cancers will involve individualized, lesion-specific, and combined therapy. In this review, the basic mechanism of each redifferentiation and molecular target therapy is discussed, and results of recent clinical trials using these therapeutic agents are summarized.