In 2014, nearly 63,000 new cases of thyroid cancer were diagnosed in the United States [1]. Medullary thyroid cancer (MTC) represents only 4%–5% of these thyroid cancers, or approximately 2800 newly diagnosed patients each year [2]. Unlike differentiated thyroid cancers that arise from follicular cells, such as papillary (PTC) or follicular (FTC) types, MTCs arise from neural crest-derived, parafollicular C-cells that possess the ability to secrete bioactive peptides and hormones, particularly calcitonin. On gross pathology, MTCs have a distinct whitish-grey, firm appearance. Histologically, they appear as uniform spindle- or polygonal-shaped cells with a fine granular eosinophylic cytoplasm and stromal amyloid (Figure 14.1) [3, 4]. These tumors exhibit a wide variety of behaviors from indolent to aggressive and are hereditary in 25% of cases. As such, the treatment, prognosis, and outcomes may also vary.