Thyroid carcinoma is the most common cancer in the endocrine system. Recent advances, using next-generation sequencing, have shed light on the molecular pathogenesis of thyroid cancer. Constitutional activation of the mitogen-activated protein kinase pathway through RAS mutation, BRAF mutation, and/or fusions involving receptor tyrosine kinase (eg, (REarranged during Transfection) RET-PTC) plays a central role in tumorigenesis and opens doors to promising tyrosine kinase inhibitor therapy. Several molecular signatures, such as TERT promoter mutation and TP53 mutation, are associated with tumor progression. This article provides a concise and updated summary of the main genetic alterations in thyroid carcinoma.