The cumulative evidence over the past decades has shown that the incidence of differentiated thyroid carcinoma (DTC) has exponentially increased. Approximately 10% of patients with DTC exhibit recurrent or metastatic disease, and about two-thirds of the latter will be defined as refractory to radioactive iodine (RAIR) treatment. Since this condition implies 10-year survival rates less than 10% after detection, using available treatments, such as systemic and targeted therapies, have become increasingly relevant. The initiation of these treatments aims to reach stabilization, tumor volume reduction, and/or symptom improvement and it should be decided by highly specialized endocrinologists/ oncologists on the basis of patient’s features. Considering that despite enlarged progression-free survival was proven, multikinase inhibitors remain non-curative, their benefits last for a limited time and the side effects potentially cause harm and quality of life reduction. In this context, molecular testing of cancer cells provides a promising spectrum of targeted therapies that offer increased compatibility with individual patient needs by improving efficacy, progression free survival, overall survival and adverse events profile. This review article aims to provide a summary of the current therapeutic strategies in advanced RAIR-DTC, including approved target therapies as well as those for off-label use, RAI resensitization agents, and immunotherapy.