Medullary thyroid carcinoma (MTC) accounts for 2–4% of thyroid cancers. It has the particularity of being a neuroendocrine tumor associated with a proto-oncogene germline RET mutation: germline in 20–25% of cases, somatic in 70–80% of metastatic sporadic cases. Locally advanced and metastatic MTCs are called “refractory”. Individual prognosis is difficult, since the clinical behavior of the disease varies greatly from one patient to another. However, histological factors, such as high-grade forms, associated with greater risk of tumor progression and death, have been recently identified, and biological factors, such as the doubling time of plasma calcitonin, may help assess prognosis. Treatment of refractory medullary thyroid carcinoma has progressed considerably over recent years, with the advent of targeted therapies such as multi-kinase inhibitors and selective RET inhibitors. Management requires multidisciplinary expertise, and is tailored to the individual clinical situation patient, the molecular characteristics of the tumor, and the progression of the disease. These advances have led the ENDOCAN-TUTHYREF rare-cancer network of the French National Institute for Cancer (INCa), dedicated to refractory thyroid cancer, to draw up a set of consensus recommendations. This article focuses on refractory medullary thyroid cancer.