Radioiodine imaging has a well-established role in depicting metastatic disease after thyroidectomy in patients with well-differentiated thyroid cancer. Uptake of radioiodine in thyroid metastases depends on expression of sodium-iodide symporter (NIS) by tumor tissues. However, because radioiodine may also accumulate in normal structures and tissues, it is important to distinguish physiologic radioiodine activity from metastatic disease. Furthermore, secretions that contain radioiodine may also simulate pathologic uptake. A spectrum of physiologic distributions, normal variants, and benign mimics of disease have been described in the literature; yet, even when armed with a comprehensive knowledge of these patterns, interpreting radiologists and nuclear physicians may still encounter diagnostic uncertainty. Single-photon emission computed tomography (SPECT) with integrated computed tomography (CT) is a novel technology that, when applied to diagnostic iodine 123 or iodine 131 ((131)I) radioiodine scintigraphy, may accurately localize and help distinguish benign mimics of disease, with the potential to alter the management plan. SPECT/CT is increasingly being used with radioiodine scintigraphy to evaluate patients with thyroid cancer and shows promise for improving imaging specificity and reducing false-positive results.