Introduction <p>Selpercatinib is a selective inhibitor of rearranged during transfection (<i>RET)</i> kinase and is indicated for patients with <i>RET</i> fusion-positive non-small cell lung cancer, advanced <i>RET</i> fusion-positive solid tumors, and thyroid cancer. This report describes a patient who developed renal tubular damage resulting in renal loss of electrolytes and polyuria four weeks after the start of selpercatinib. To our knowledge, tubular damage is a rare selpercatinib-induced toxicity. This report contributes to the growing literature about selpercatinib-related adverse events and their management.</p> Case <p>A 74-year-old male with <i>RET</i> mutation-positive medullary thyroid cancer, presented with thirst, hyponatremia, hypomagnesemia, hypocalcemia, and polyuria. The hyponatremia deteriorated to symptomatic hyponatremia (112 mmol/L) and required intensive care unit admission. Selpercatinib treatment (160&#xa0;mg bi-daily) was interrupted, and plasma was collected for therapeutic drug monitoring (TDM). The patient was hospitalized for fluid supplementation and correction of electrolytes. The association with selpercatinib seemed likely due to a Naranjo score of 9 (out of 13). Following dose interruption and supportive care, electrolyte disturbances and polyuria resolved. After recovery, selpercatinib was rechallenged at a dose of 80&#xa0;mg bi-daily based on TDM. No recurrence of electrolyte disturbances or renal toxicity was observed, and the patient maintained stable disease.</p> Conclusion <p>Our report indicates an association between selpercatinib plasma concentration and renal tubular damage, and emphasizes the importance of recognizing selpercatinib-induced tubular injury. This report also provides guidance for the management of these renal manifestations and for rechallenge guided by TDM, highlighting a potential role for TDM in dose determinations after selpercatinib-induced renal toxicity.</p>