Radioactive iodine is an effective first line therapy for follicular cell neoplasms of the thyroid gland. Around 5% of cases will be at outset, or become over time refractory to radioactive iodine (RAIRD) and these patients have much poorer prognosis (10% 10-year survival). Tyrosine kinase inhibitors (TKIs) have recently become available for this cohort and can show an increase in progression free survival, but selecting which patients will best respond to these drugs is not yet established. Genetic events in thyroid cancer are well characterised in the literature and include RAS (H, K, N), BRAF, NTRK1, or RET rearrangements. The Royal North Shore experience, as a quaternary referral centre sees >200 new cases/year. Next generation sequencing has become widespread for molecular profiling of key cancer genes. We have used these techniques and others to profile molecular events in RAIRD patients, and where possible sought targeted therapies to improve patient outcomes. This has led to establishing a practice of precision medicine where these patients with identifiable driver mutations have new options for treatment. In anaplastic thyroid cancer the distinction between BRAF +/- disease is crucial to the response to MEK inhibition. Furthermore in differentiated thyroid cancer, non targeted TKIs (lenvatinib) are used, but the the small patient cohort with RET or NTRK1 mutations have more selective options. Lastly, this strategy has led to enrolment of phase I and II trials in targeted therapies including the highly selective RET inhibitor LOXO-292 at our clinical trials unit. We describe our experience of panel testing in identifying practice changing variants in a small (18) but growing number of patients. As we move to this personalised medicine approach, finding funding and accessing these therapies remains a challenge.