During the past two decades, several key somatic mutations associated with 
development and progression of differentiated thyroid cancer (DTC) have been 
revealed. Historically, the treatment for advanced DTC is challenging after 
patients become refractory to radioactive iodine. The response to doxorubicin, 
the only chemotherapy agent approved by the US Food and Drug Administration, is 
disappointing either as monotherapy or combination therapy. Because of the lack 
of effective systemic treatment coupled with increased understanding of 
molecular and cellular pathogenesis, multiple kinase inhibitors (MKIs) as an 
alternative therapy for the treatment of advanced DTC has generated much 
interest, enthusiasm, and, most excitingly, promising results. After the 
encouraging results of these agents in earlier trials, the Food and Drug 
Administration approved sorafenib for the treatment of locally recurrent, 
progressive, or metastatic DTC refractory to radioactive iodine treatment based 
on the results of a multicenter DECISION trial. Sorafenib therefore became the 
first MKI approved for this indication in more than 20 years. However, even more 
impressive responses and progression-free survival benefits were seen in the 
phase III SELECT trial with lenvatinib, giving even higher hopes for the future 
management of what was considered just a decade ago an orphan disease. Given the 
role of MKIs, a new era in the treatment of advanced DTC has begun. We review 
the key therapeutic targets, oncogenic pathways, and promising clinical results 
of these agents in refractory disease, as well as their roles after failure of 
first line kinase inhibitors.