Thyroid cancer (TC) is the most common endocrine malignancy with steadily increasing incidence over the past few decades. Although standard strategies for the management of TC offer optimal outcomes in TC patients with favorable histological types at early stage, challenges arising from diagnosis and therapy still exist during clinical practice. A number of genetic alterations have been described in thyroid cancer, which provides an unprecedented opportunity for the identification of novel diagnostic and prognostic molecular markers as well as novel therapeutic targets. Molecular-targeted therapies, which have been investigated recently with increasing success, may prove to be a breakthrough in patients with advanced, radioiodine-refractory thyroid cancers. This review summarizes the latest progression in molecular diagnosis and targeted therapy of TC.