Although thyroid abnormalities are reported with the use of tyrosine kinase inhibitors, patients rarely require replacement therapy. The initial multicentre studies of sunitinib for metastatic renal cancer did not report hypothyroidism in fatigued patients, and thyroid tests were not routinely monitored. More recent studies, however, suggest that up to 70% of patients develop thyroid test abnormalities during treatment with sunitinib. Despite these concerns, the clinical relevance of sunitinib-induced hypothyroidism is uncertain since thyroid gland recovery is the norm in most patients. We report a case of a patient with metastatic papillary renal cell cancer on combination anti-angiogenic therapy with sunitinib, who developed unusually high thyroid stimulating hormone levels and severe symptoms despite receiving L-thyroxine. Our case also illustrates the complexity of managing sunitinib-associated thyroid dysfunction, which may be accompanied by transient thyroiditis, hyperthyroidism, and profound hypothyroidism.