Germline missense mutations in the RET oncogene are the cause of Multiple Endocrine Neoplasia type 2 (MEN2) but at present surgery is the only treatment available for MEN2 patients. In this study, the ability of Sorafenib (BAY 43-9006) to act as a RET inhibitor was investigated. Sorafenib inhibited the activity of purified recombinant kinase domain of wild type RET and RETV804M with IC50 of 5.9 nM and 7.9 nM, respectively. Interestingly, these values were 6- to 7-fold lower than the IC50 for the inhibition of B-RAFV600E. In cell based assays, Sorafenib inhibited the kinase activity and signaling of wild type and oncogenic RET in MEN2 tumor and established cell lines at concentration between 15 and 150 nM. In contrast, inhibition of oncogenic B-RAF- or EGF-induced ERK1/2 phosphorylation required micromolar concentrations of Sorafenib demonstrating the high specificity of this drug in targeting RET. Moreover, prolonged exposure to Sorafenib resulted in inhibition of cell proliferation and RET protein degradation. Using lysosomal and proteasomal inhibitors we demonstrate that Sorafenib induces RET lysosomal degradation independent of proteasomal targeting. Furthermore, we provide a structural model of the Sorafenib-RET complex in which Sorafenib binds to and induces the DFGout conformation of the RET kinase domain. These results strengthen the argument that Sorafenib may be effective in the treatment of MEN2 patients. In addition, as inhibition of RET is not impaired by mutation of the Val804 gatekeeper residue, MEN2 tumors may be less susceptible to acquired Sorafenib resistance.