The incidence of thyroid cancer has risen in recent decades, largely due to the widespread use of increasingly sensitive imaging techniques that have enhanced the detection of thyroid nodules. Fine-needle aspiration cytology remains the diagnostic gold standard; however, 15–25% of samples fall into indeterminate Bethesda categories (III and IV), for which the traditional approach often involves diagnostic surgery, despite around 75% of these nodules ultimately prove to be benign. Advances in the genetic characterization of thyroid tumors, together with the development of next generation sequencing (NGS) technologies, have enabled the introduction of molecular tests aimed at improving preoperative risk stratification. Key genetic alterations include mutations in BRAF, the RAS family, the TERT promoter, and rearrangements involving RET, NTRK, and ALK, all of which have diagnostic and prognostic implications. Several commercial assays have been developed, employing methodologies including NGS, RNA sequencing, microRNA profiling, and qPCR. These tests demonstrate good sensitivity and high negative predictive value, helping to reduce unnecessary surgeries and better guide therapeutic decisions. Alongside commercial platforms, the high cost and limited accessibility of such tests have stimulated the development of increasingly robust in-house panels. Integrating molecular profiling with clinical and ultrasound findings now enables a more personalized approach to the management of indeterminate thyroid nodules, including surgery, mini-invasive treatments or active surveillance. Future perspectives include multi-omic and artificial intelligence approaches, which may further enhance diagnostic accuracy and cost-effectiveness.