Molecular genetics analyses have indicated that approximately 55% of medullary thyroid cancer (MTC) tumors bear activating mutations of the RET gene, including inherited and sporadic cases. Tumoral RET mutations, especially M918T, have a strong negative prognostic impact. RET is the most important target for recent systemic therapy trials of MTC, along with vascular endothelial growth factor receptors. This review discusses promising recent clinical trials data for multikinase inhibitors including motesanib, vandetanib, sunitinib, sorafenib, and cabozantinib/XL184. Across multiple studies reported to date, RET mutations, although prevalent in these subjects, have not proven so far to predict whether patients will respond to multikinase inhibitors. In addition to comparing available data for efficacy and toxicity of these agents, the review focuses on critical questions related to appropriate selection of MTC patients for systemic treatment, and how best to integrate these therapies with established modalities of surgery and radiation therapy.