The catalytic subunit (p110a) of phosphatidylinositol-3-kinase (PI3K) is encoded by the PIK3CA gene and acts to activate several signaling cascades, including the well-characterized AKT-mTOR pathway that promotes cell survival, proliferation, growth and motility. PIK3CA is among the most commonly mutated genes in cancer and aberrant activation of PI3K is a transforming event. Somatic mutations in PIK3CA are seen in approximately 2% of papillary thyroid carcinoma, poorly differentiated carcinoma, anaplastic carcinoma. Somatic mutations of PIK3CA have been described particularly in advanced and dedifferentiating thyroid tumors. Their prevalence varies from 16 to 23% in anaplastic thyroid carcinomas. They are less frequent in papillary and follicular thyroid carcinomas and the prevalence in medullary thyroid carcinomas remains unknown. Although inhibitors of the PI3K/AKT/mTOR pathway have shown efficacy against thyroid cancer in pre-clinical models, their success in clinical trials remains to be determined.