Radioactive-iodine-refractory differentiated thyroid cancer (RAIR DTC) represents 3–5% of follicular-derived DTCs, with approximately 200–300 new cases diagnosed annually in France. Median overall survival in the French RAIR DTC database is 9.5years, underscoring the importance of long-term support for caregivers and patients. To guide treatment decision-making, the French ENDOCAN TUTHYREF network has provided algorithms for RAIR DTC management, available at the TUTHYREF website. The present article summarizes these recent practical recommendations, focusing on 5 points. (1) RAIR DTC has long been defined by locally advanced disease not amenable to surgery or metastatic disease not fully responding to radioactive iodine (RAI) therapy, a definition that can be further refined considering prognostic factors. (2) Treatment should be tailored according to tumor burden and progression, with local treatments prioritized for non-progressive or slowly progressive disease. (3) Early tumor molecular testing should be performed to identify driver oncogenes such as BRAF mutation or RET/NTRK/ALK fusion, to optimize access to existing selective targeted therapies. (4) For symptomatic or progressive RAIR DTC, tyrosine multikinase inhibitors, such as sorafenib, lenvatinib or cabozantinib, are the standard therapies, but alternative and 2nd-line kinase inhibitors are also available. (5) Since most therapies are associated with common side-effects such as fatigue and cardiovascular, digestive and skin issues, preparing and monitoring patients for systemic therapy should include careful assessment of comorbidities, toxicity prevention and individual dose adjustment. Overall, management of RAIR DTC requires a multidisciplinary approach, with an emphasis on personalized treatment strategies and proactive therapeutic education.