Until recently, patients with advanced thyroid cancers had limited options for systemic treatment. With the introduction of tyrosine kinase inhibitors (TKIs) as a promising new class of targeted therapies for thyroid cancer, suddenly patients with advanced disease were given new options to extend survival. Guidelines worldwide have been updated to include general indications for these newer agents, but questions remain regarding which agent(s) to select, when to begin treatment, and how long therapy should continue. Additionally, the true impact of TKIs on overall survival and quality-of-life in thyroid cancer patients needs further clarification. As familiarity with approved agents and longer-term data become available, better strategies for implementation of these targeted drugs will evolve to optimize benefit for patients living with metastatic disease.