Radioiodine treatment following surgery is an effective therapy in differentiated thyroid carcinoma (DTC) patients. However, in DTC patients with metastases characterized by very low or absent iodine uptake, total thyroidectomy and radical loco-regional lymphoadenectomy is the only effective therapeutic approach. In the present article, we have discussed the most recently available nuclear medicine techniques utilized for the detection of DTC metastases that have lost the capacity to trap radioiodine. A review of the data published in the literature has been presented, and a comparative analysis made of the results obtained by other imaging modalities such as high resolution neck ultrasonography (US), computed tomography (CT) and magnetic resonance imaging (MRI). In our experience, the most sensitive and accurate imaging procedure is represented by the combination of neck US and whole body 99mTc-methoxy-isobutylisonitrile (99mTc-MIBI) scintigraphy; this combination might be proposed as a first-line diagnostic approach in DTC patients with increased serum thyroglobulin (Tg) levels and negative high dose 131I scans.