| Summary: | Thyroid cancer is the most common malignancy of the endocrine system. Fine-needle aspiration (FNA) biopsy of thyroid nodules has become the gold standard procedure, in terms of cost and efficacy, for guiding clinicians towards appropriate patients’ management. One challenge for cytopathologists is to accurately classify cytological specimens as benign or malignant based on cytomorphological features. In fact, with a frequency ranging from 10% to 30%, nodules are diagnosed as indeterminate. In recent years, the mutational landscape of thyroid tumors has been extensively described, and two molecular profiles have been identified: <i>RAS</i>-like (<i>NRAS</i>, <i>HRAS,</i> and <i>KRAS</i> mutations; <i>EIF1AX</i> mutations; <i>BRAF K601E</i> mutation; and <i>PPARG</i> and <i>THADA</i> fusions) and <i>BRAF</i><sup>V600E</sup>-like (including <i>BRAF</i><sup>V600E</sup> mutation and <i>RET</i> and <i>BRAF</i> fusions). The purpose of this review is to discuss the latest molecular findings in the context of indeterminate thyroid nodules, highlighting the role of molecular tests in patients’ management.
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