Understanding the molecular landscape of papillary thyroid carcinoma (PTC), the most common thyroid cancer in children, creates additional therapeutic approaches. RET gene rearrangements are observed in pediatric PTC and selective inhibition of RET is now possible with specific tyrosine kinase inhibitors designed to target diverse RET-activating mutations. We present a 13-year-old female with radioactive iodine-refractory metastatic PTC, found to harbor a NCOA4-RET fusion, who responded to treatment with selpercatinib with elimination of supplemental oxygen need, marked reduction in pulmonary nodules and mediastinal lymphadenopathy, and substantial improvement in thyroglobulin levels. Response was maintained despite 2 dose reductions for possibly-related weight gain.