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Purpose: This article aims to comprehensively analyze the unique challenges in managing patients with metastatic Differentiated Thyroid Cancer (DTC) that develop radioiodine-refractory disease, especially in developing countries in Latin America. We discuss key contentious aspects of their treatment, such as the optimal timing for initiating systemic therapy, the choice of first-line medications, the appropriate timing for requesting molecular interrogation, and the challenges associated with accessing these drugs and molecular panels., Methods: To illustrate these challenges and enhance understanding, we present five real clinical cases from the authors' experiences., Results: Patients with Differentiated Thyroid Cancer (DTC) generally have an excellent prognosis, with an overall 10-year survival rate exceeding 97%. However, approximately 5% of DTC patients, especially those with distant metastases, may develop radioiodine-refractory disease, reducing survival rates. Access to medications remains difficult and time-consuming, particularly for patients within the public healthcare system. Urgent discussions on drug pricing involving all stakeholders are imperative. To break free from complacency, stakeholders must prioritize patient well-being by advocating for evidence-based drug pricing, increased participation in clinical trials, and streamlined regulatory processes., Conclusion: Beyond the recognized need for prospective randomized clinical trials to determine the optimal first-line drug and the timing of molecular testing, this type of manuscript plays a pivotal role in stimulating discussions and disseminating comprehensive knowledge about the challenges associated with treating and monitoring patients with radioiodine-refractory thyroid carcinoma, especially in developing countries., Competing Interests: Compliance with ethical standards Conflict of interest Gustavo C. Penna is a speaker and participant of the Advisory Boards for Ipsen and Knight. Fabian Pitoia is a speaker and participated in Advisory Boards for Bayer and Raffo, PI Bayer, Roche, and Novartis. Aline L. F. Chaves is a speaker and participates in Advisory Boards for Merck Serono, Merck Sharpe and Dhome, Ipsen, Knight, Bayer, Eli Lilly. Kamilla M. A. Brandão Rajão is a speaker for Knight. The other authors have no financial interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)