Anaplastic thyroid carcinoma (ATC) is a rare, but devastating disease. Despite multimodal approaches combining surgery, chemotherapy and radiation therapy, ATC is associated with a dire prognosis, with a median overall survival of only three to ten months. Novel treatments are thus urgently needed. Recent efforts towards the characterization of the molecular landscape of ATC have led to the identification of pro-oncogenic targetable alterations, lending promise for novel targeted therapeutic approaches. This systematic review summarizes the results of phase II clinical trials of targeted therapy in ATC, providing an overview of efficacy and safety profiles. The majority of trials to date have consisted of small single-arm studies and have presented modest results. However, only a minority of trials have selected or stratified patients by molecular alterations. In the setting of BRAF V600E mutated ATC, dabrafenib/trametinib combination therapy and vemurafenib monotherapy have both demonstrated efficacy. Everolimus has furthermore shown promising results in patients with PI3K/mTOR/AKT pathway alterations. These studies underscore the importance of molecular profiling of tumors for appropriate patient selection and determination of genomic correlates of response. Clinical trials are underway testing additional targeted therapies as monotherapy, or as a part of multimodal treatment, and in combination with immunotherapy.