Thyroid cancers stand out among solid tumours because many of the tumour-initiating genetic events have been identified. Mutations leading to constitutive activation of MAP kinase effectors -the tyrosine receptor kinase RET and the intracellular signalling effectors RAS and BRAF- are essential for the pathogenesis of papillary thyroid carcinoma (PTC). Similarly, there is increasing evidence demonstrating that mutations leading to activation of the phosphatidylinositol 3- kinase (PI3K)/AKT effectors -PTEN and PI3KCa- are essential for the pathogenesis of follicular thyroid carcinoma (FTC). Besides this strong relationship between the histological phenotype and the pathway predominantly activated, the nature of the genetic event seems to determine the biological behaviour of the tumour and the ultimate clinical outcome of the patient. In this review we will summarise and discuss the main genetic events related to thyroid cancer initiation, the contribution of genomics and the convenience of using a new molecular classification of thyroid cancer, complementary to the clinicopathological classification. This may help us to predict more faithfully the clinical outcome of patients with thyroid cancer and to select more appropriately candidates for targeted therapies.