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Background: Medullary thyroid cancer (MTC) is a rare neuroendocrine tumor originating from parafollicular C-cells. It represents 2% of all thyroid malignancies and 0.4-1.4% of all thyroid nodules. MTC has a variable clinical course, with complete remission often difficult to achieve. An early diagnosis is still crucial in MTC management, enabling a radical surgical treatment, the only chance for curing the patient. Calcitonin (Ct) is a very sensitive MTC tumor marker in patients with thyroid nodules, although Ct-negative MTCs have been described, but not all clinical guidelines recommend the Ct routine measurement in thyroid nodules because of the absolute low prevalence of MTC in the general population and the consequent scarce positive predictive value of Ct. Moreover, the specificity of moderately high Ct levels is not high. Thus, the scientific community has been investigating the possible role of other tumor markers for MTC diagnosis and prognosis. Aim of the review: The present review is an attempt to summarize the knowledge available today on the role of other serum markers for MTC alternative to Ct. Conclusions: At present, literature data does not seem solid enough yet to establish effective flowcharts in evaluating a thyroid nodule for MTC, involving alternative serum markers, particularly in cases of moderately high CT levels. MTC is a rare diagnosis in thyroid nodules, and this makes the evaluation of any tumor serum marker accuracy problematic. More extensive and prospective studies are needed to shed more light on this intriguing challenge. [ABSTRACT FROM AUTHOR]