Thyroid cancer is one of the most common endocrine malignancies and in the last two decades the number of involved people in the world has been increased. Thyroid cancer in Iran is the seventh most common cancer in women and 14th in men. In recent years many achievements regarding to molecular pathogenic factors such as the substantial role of signaling pathways and molecular abnormalities have been made. Nowadays there is no efficient treatment for progressed thyroid cancer that does not respond to radioiodine therapy which are included poorly differentiated, anaplastic and metastatic or recurrent differentiated thyroid cancer. Although the results of some clinical trials in phase II for treatment of progressed thyroid cancer are rewarding but none of the treated patients responded to treatment and only a few of them responded partially to the treatment which indicates that the treatment can only control the condition of patients with advanced disease, therefore it is needed to consider other alternative solutions which would be helpful in controlling the disease. Epigenetic is referred to study of heritable changes in gene expression without changes in primary DNA sequence. The main mechanisms of genetic and epigenetic alterations are including mutations, increasing the gene copy number and aberrant gene methylation. Epigenetic defects are prevalent in different types of cancers. Aberrant methylation of genes that control cell proliferation and invasion (p16INK4A, RASSF1A, PTEN, Rap1GAP, TIMP3, DAPK, RARβ2, E-cadherin, and CITED1), as well as specific genes involved in differentiation of thyroid cancer (Na+/I- symport, TSH receptor, pendrin, SL5A8, and TTF-1) in association with genetic alterations, leads to tumor progression. Growing evidence shows that acquired epigenetic abnormalities participate with genetic alterations to cause altered patterns of gene expression or function. Many of these molecular changes can be used as molecular markers for prognosis, diagnosis and new therapeutic targets for thyroid cancer. This article is about the most common genetic and epigenetic alterations in thyroid cancer which can be complementary together in recognition of new treatments for the disease.