Growing evidence supports the concept of oncogene dependence for cancer development; inhibition of the initiating oncogene can result in revertion of the neoplastic phenotype. The outstanding role of the RET proto-oncogene in the development of medullary thyroid carcinoma (MTC) is well established. With the emerging knowledge concerning the signal transduction pathways leading to subsequent neoplastic transformation, oncogenic activated RET becomes a highly attractive target for selective cancer therapy. A variety of novel approaches that target RET directly or indirectly have recently emerged and an increasing number are currently being assessed in clinical trials. In view of these findings, it becomes strikingly obvious that inhibition of RET oncogene function can be a viable option for the treatment of MTC. We summarize the current evidence for RET involvement in the etiology of MTC, and the therapeutic targeting of this process in preclinical and clinical studies.