The limited therapeutic options available for patients with metastatic papillary thyroid carcinomas (PTC) and follicular thyroid carcinomas (FTC) necessitates the development of novel therapies. Identification of somatic rearrangements of the tyrosine kinase domain of the RET gene in PTC have improved our understanding of thyroid tumorigenesis. Sunitinib is active against the RET kinase and has both antineoplastic and antiangiogenic properties. Its role in the treatment of patients with thyroid carcinoma has yet to be evaluated in clinical trials. Two patients with progressive metastatic thyroid carcinoma (case 1: PTC, and case 2: FTC) were enroled in a phase I clinical trial to evaluate positron emission tomography (PET) in the monitoring of response to sunitinib. Tumour biopsies and PET were performed at baseline and 4 weeks after the commencement of sunitinib. Activation of the RET kinase pathway was evaluated using immunohistochemistry (IHC) and western blot analysis of total phosphorylated tyrosine and downstream signalling targets of the RET pathway. Both patients demonstrated sustained clinical responses to sunitinib over a duration of 4 years. In case 1, (PTC) PET confirmed evidence of a partial metabolic response, and IHC and western blot analysis demonstrated inhibition of the RET kinase pathway posttreatment. In case 2, (FTC) PET confirmed stable disease after sunitinib. IHC staining of the tumour showed low total phosphorylated tyrosine staining at baseline which did not change after treatment. These case studies highlight potential activity of sunitinib in patients with metastatic thyroid carcinoma. Sunitinib seems to be a promising agent in the treatment of thyroid cancers and this requires validation in future clinical trials.