Medullary thyroid cancer (MTC) is an infrequent calcitonin-secreting thyroid malignancy that can vary a great deal in tumor biology and progression. The most important determinant of distant metastases, which represents the single greatest risk factor of poor cancer-specific survival, is lymph node metastasis in the neck and mediastinum. In patients with node-positive MTC, systematic compartment-oriented dissection of central and lateral neck nodes at the initial operation promotes biochemical cure and decreases the risk of locoregional recurrence in previously dissected lymph node compartments. Routine calcitonin screening in nodular thyroid disease and genomic screening, flanked by advances in ultrasound and functional imaging modalities, have been pivotal in making the diagnosis early and enabling risk-reducing surgical interventions in patients with sporadic and hereditary MTC, without compromising clinical outcome. To assess a RET carrier’s risk of medullary thyroid cancer, all that is needed is patient age, underlying RET mutation, and biomarker levels. Recently, risk-reducing surgery, consisting in hemithyroidectomy with or without diagnostic ipsilateral central lymph node dissection, has been advocated for sporadic MTC clinically confined to one thyroid lobe that is desmoplasia negative on intraoperative frozen sectioning. These recent developments reflect the current shift from reactive to increasingly preemptive, risk-reducing surgery for MTC.