Objective To summarize the advance in targeted therapy for radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC). Method The literatures relevant to the targeted therapy for RAIR-DTC were reviewed and summarized. Results Targeted therapy for RAIR-DTC mainly included multi-kinase inhibitors suppressing angiogenesis and mutation-specific kinase inhibitors targeting specific mutations. Representative multi-kinase inhibitors such as sorafenib and lenvatinib, which significantly prolonged progression-free survival, had been approved to put into clinical use, though there were shortcomings such as adverse effects and resistance. Mutation-specific kinase inhibitors acted on targets such as RET, mitogen-activated protein kinase pathway, phosphoinositide 3-kinase pathway respectively, with relatively small side effects, most of which had only been applied in clinical trials up to now. Conclusions Targeted therapy for RAIR-DTC has made rapid progress in recent years, filling the gap in treatment for RAIR-DTC. Further explorations and investigations are needed to establish a more effect and safer treatment mode.