Radioactive iodine (RAI) refractory thyroid cancer has a poor prognosis. Research to re-differentiate thyroid cancer to restore iodine avidity is one approach being pursued to improve clinical outcomes. This presentation will explore the current knowledge in this field including the I-FIRST trial, an MRFF funded prospective multi-centre study aiming to demonstrate restoration of RAI uptake to facilitate effective I-131 treatment. The trial is actively recruiting with a rational treatment approach using short-term mutation directed tyrosine kinase inhibitor therapy (MEK-inhibitor if NRAS mutant or MEK/BRAF inhibitor if BRAF-V600E mutant), thyroxine withdrawal TSH stimulation and dosimetric I-124 PET to guide the suitability for RAI therapy.