Medullary thyroid carcinoma (MTC) is a rare disease that is indolent in the majority of patients. In a subset of patients, the cancer is more aggressive with symptomatic or progressive disease metastasizing to cervical neck structures, lungs, liver, and/or bones. Definitive cure for metastatic MTC remains elusive. Understanding oncogenic pathways and molecular drivers of disease have led to development and approval of multikinase and highly-specific RET inhibitors for the management of progressive MTC. RET mutations are the most common drivers in MTC, followed by mutually exclusive RAS mutations. Cabozantinib and vandetanib, multikinase inhibitors (MKIs) that exert their therapeutic effect mainly through antiangiogenesis by targeting the vascular endothelial growth factor receptor, have mild anti-RET activity. Despite conveying clinical responses in MTC, MKIs have significant off-target activity causing marked toxicities limiting their effectiveness. Potent and selective RET inhibitors, selpercatinib and pralsetinib, demonstrate significant efficacy in RET-altered cancers and more tolerable side effect profiles than MKIs. However, durable responses can be limited by the acquisition of mutations which confer drug resistance to available treatments. Thus, development of more effective treatments for advanced, progressive MTC remains an urgent priority. In this chapter, we describe the current spectrum of systemic therapies for MTC, their limitations, and ongoing investigations.