Thyroid cancer is the most common endocrine malignancy worldwide. However, there is not a definite treatment for advanced thyroid cancer, which comprises poorly differentiated, anaplastic and metastatic or recurrent differentiated thyroid cancer that do not response to radioiodine; treated patients had not a complete response. Biological therapies have been proposed on the basis of the recognition key oncogenic mutations and these treatments could be effective in stabilizing progressive disease. Epigenetic abnormalities are present in almost all cancers and together with genetic variations led to tumor progression. Rap1, a member of RAS family of small GTPase has been implicated in regulation of mitogenic and oncogenic pathways in thyroid, and its CpG island methylation is reported in some kind of tumors. In addition, miRNAs play important role in cell differentiation, proliferation and survival. They considered as the regulators of gene expression at posttranscriptional level. Deregulation of miRNAs expression is suspected to be an important regulator of tumor development and progressive. Epigenetic modification pattern is different not only between normal and tumors tissues, but also between different stage of malignancy and between primary and metastatic tumor. Therefore these variations may become useful novel biomarkers for diagnostic and treatment tumors.