Thyroid cancer is a heterogeneous disorder characterized by gene mutations that activate signaling pathways, and also by abnormalities in tumor suppressor genes and cell cycle proteins. Activation of the Akt / PKB signaling pathway appears to be an important event in thyroid tumorigenesis and, perhaps, in tumor progression too. Akt is activated in Cowdens syndrome through inactivation of PTEN, a negative regulator of Akt. Cowdens syndrome is an autosomal dominant multiorgan hamartoma syndrome characterized by benign and malignant thyroid tumors, breast cancers, and colon cancers. In addition, the Akt pathway appears to be activated in a significant proportion of sporadic thyroid cancers through activation of growth factor pathways by thyroid oncogenes and / or receptor overexpression. Disruption of PI3-kinase activity pharmacologically or disruption of Akt signaling using dominant negative cDNA expression have demonstrated salutary effects on several cancer models in vitro. Therefore, Akt represents an attractive target for pharmaceutical development for a variety of malignancies, including thyroid cancer.