Anaplastic thyroid cancer (ATC) is among the most aggressive cancers with a median overall survival of 4 months and a disease-specific mortality of close to 100%. As soon as the diagnosis is suspected or established, urgent referral to an experienced multidisciplinary center is imperative. Chemotherapy has limited efficacy. Molecular analyses, together with the availability of novel targeted therapies and immunotherapies, now permit to improve outcomes. In particular, targeted therapy with dabrafenib and trametinib is indicated as first-line therapy for BRAF V600E-mutated ATC.