In this report, we present a patient with MTC harboring a previously uncharacterized RET activation loop deletion mutation (p.D898_E901del), who had a nice response to selpercatinib but developed target-bypass secondary, tertiary and quaternary genetic lesions as resistance mechanisms after 24 months of the RET-targeted therapy. The gene discussed is RET; the disease is medullary thyroid gland carcinoma.