Thyroid papillary carcinoma is the most common type of endocrine cancer. It is frequently associated with genetic alterations leading to activation of the MAPK signaling pathway. The two most frequently affected genes, BRAF and RET, are activated by either point mutation or as a result of chromosomal rearrangement. These mutations are tumorigenic in thyroid follicular cells and correlate with specific phonotypical features and biological properties of papillary carcinomas, including tumor aggressiveness and response to radioiodine therapy. Molecular inhibitors that block RET/PTC or BRAF kinase activity have shown substantial therapeutic effects in the experimental systems and are currently being tested in clinical trials.