Medullary thyroid carcinoma (MTC) is a rare type of thyroid cancer, demonstrating variable behavior from indolent disease to highly aggressive, progressive disease. There are distinguishing phenotypic features of sporadic and hereditary MTC. Activation or overexpression of cell surface receptors and up-regulation of intracellular signaling pathways in hereditary and sporadic MTC are involved in the disease pathogenesis. There has been an exponential rise in clinical trials with investigational agents, leading to approval of 2 medications for progressive, advanced MTC. Developments in understanding the pathogenesis of MTC will hopefully lead to more effective and less toxic treatments of this rare but difficult to treat cancer.