Papillary thyroid cancers are the most common thyroid malignancy. They usually carry a favorable prognosis, although patients with invasive or metastatic tumors that no longer trap radioiodine do less well. There is mounting experimental support for a central role of mutations leading to constitutive activation of MAP kinase effectors in the pathogenesis ofthis disease. Thus activating mutations of the tyrosine receptor kinases RET and NTRK, and of the intracellular signaling effectors RAS and BRAF are present in a mutually exclusive fashion in more than 70% of cases. These mutations are believed to arise at early stages of cancer development, and may be important in tumor maintenance. Hence, compounds that inhibit kinase activity of effectors signaling distally along this pathway may prove effective in treating advanced forms of the disease.