Tyrosine kinase inhibitors (TKIs) have revolutionised systemic therapy for advanced thyroid cancers, including radioiodine-refractory differentiated thyroid cancer (RR-DTC), anaplastic thyroid cancer (ATC) and medullary thyroid cancer (MTC), which respond poorly to conventional cytotoxic chemotherapy. The treatment of advanced thyroid cancer is also increasingly personalised, with recent advances in genomic-driven, highly selective targeted therapies. This review summarises contemporary evidence regarding the efficacy, safety and clinical application of drug therapies in thyroid cancers, whilst exploring their evolving role in the age of personalised medicine. Multikinase inhibitors (MKIs) such as sorafenib, lenvatinib, vandetanib and cabozantinib have demonstrated significant improvements in progression-free survival and objective response rates in patients with RR-DTC and MTC. In ATC-a highly lethal tumour-BRAF-directed therapies have shown promising efficacy in patients harbouring the BRAF V600E mutation, yielding enhanced survival outcomes. Moreover, highly-selective inhibitors targeting RET, NTRK and other actionable alterations have refined treatment paradigms by increased integration of molecular testing via next-generation sequencing, ensuring treatments are tailored to the genetic profile of an individual tumour. Despite significant progress, management of advanced thyroid cancer remains challenged by drug resistance and toxicity, underscoring the need for ongoing research and innovation. Furthermore, vast improvements are still required to ensure universal access to molecular testing and targeted therapies.