Anaplastic thyroid cancer is a rare aggressive malignancy resulting in poor outcomes, including significant morbidity and mortality. Historically, the overall survival of patients with anaplastic thyroid cancer has been less than 12 months. Multidisciplinary approaches combining surgery, radiation, and chemotherapy have been implemented to control this ominous disease. The evolution in science and technology has promoted deeper knowledge in the genetic pathways and mechanisms driving advance thyroid cancer. Furthermore, understanding molecular pathways resulted in the application of antineoplastic agents used in other tumors to thyroid cancer and the development of new highly selective drugs. A major landmark in anaplastic thyroid cancer management history was recently reached with the approval of BRAF and MEK inhibitor combination, specifically dabrafenib and trametinib for BRAF-mutated anaplastic thyroid cancer; this treatment has improved survival and outcomes in this population. Similarly, newer kinase inhibitors and immunotherapy are further shifting advanced thyroid cancer management to consider as first-line therapy inhibiting actionable oncogenic alterations. Therefore, newer treatment paradigms are incorporating molecular testing to provide personalized cancer care in anaplastic thyroid cancer. In this review, the principal aim is to provide an overview of the available international data on tyrosine kinase inhibitors and immunotherapy in the management of anaplastic thyroid cancer.