Thyroid cancer incidence is increasing all over the world -mostly due to an increase in the detection of small tumors that were previously undetected. A small percentage of these tumors lose the ability to uptake and/or to respond to radioiodine (RAI) therapy, especially in metastatic patients. There are several new therapeutic options that have emerged in the last 5 years to treat RAI refractory thyroid cancer patients, however, it is very important to properly identify RAI refractory patients and to clarify those appropriate for these treatments. In this review, we discuss the RAI refractory definitions and the criteria that have been suggested based on RAI uptake in the post therapy scan, as well as the response after RAI therapy and the possible molecular mechanisms involved in this process. We offer a review of the therapeutic options available at the moment and the therapeutic considerations based on a patient's individualized personal characteristics, primary tumor histology, tumor burden and location and velocity of lesion growth.