Genetic alterations leading to the activation of the MAPK and PI3K/AKT signaling pathways play a crucial role in thyroid cancer development and progression. This can be exploited in tumor diagnosis, prognostication, and targeted therapy. Specifically, molecular testing for a panel of mutations consisting of BRAF, RET/PTC, RAS, and PAX8/PPARγ significantly improves the FNA diagnosis of thyroid nodules and can be used to optimize the surgical and post-surgical management of patients with thyroid cancer.