Radioiodine is a central treatment modality for differentiated thyroid cancer. Whilst its utility for post-surgery ablation in some patients remains controversial, the importance of radioiodine in the treatment of recurrent and metastatic disease is clear. Advanced disease which no longer takes up radioiodine (radioiodine-refractory DTC (RR-DTC)) is commonly associated with a poor prognosis, with 10-year survival rates for metastatic RR-DTC <10%. Although new systemic therapies for RR-DTC look promising in clinical trials, the development of drug resistance and significant toxicities highlights the ongoing requirement for alternative strategies. One such strategy is the restoration of radioiodine uptake to enable effective radioiodine treatment. Exploring this approach has emphasised a need to understand exactly how radioiodine uptake, mediated by the sodium iodide symporter (NIS), is regulated and how it is repressed in RR-DTC. NIS expression is downregulated in thyroid cancer, particularly in RR-DTC, and recent approaches have focused on the reinduction of NIS expression using redifferentiation agents such as retinoids or through inhibition of the MAPK pathway, the latter resulting in encouraging clinical trial outcomes. Correct targeting of NIS to the plasma membrane is also essential for efficient radioiodine uptake. Our work identified the first known molecule to interact with NIS and modulate its function. Pituitary tumor-transforming gene-binding factor (PBF) binds NIS and induces its internalisation. This interaction is mediated by PBF phosphorylation by Src kinase and Src inhibitors prevent PBF-mediated repression of NIS. We continue to evaluate the potential clinical utility of Src/PBF inhibition in restoring radioiodine uptake and are currently investigating two further novel interactors of NIS which modulate its function; ADP-ribosylation factor 4 (ARF4) and valosin containing protein (VCP). Taken together, a combination of drug treatments that induce both NIS expression and membrane localisation is likely to be required for maximum restoration of radioiodine uptake in RR-DTC.